Pharmaceutical Research

, Volume 32, Issue 8, pp 2477–2502 | Cite as

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

  • Robert Gharavi
  • William Hedrich
  • Hongbing Wang
  • Hazem E. Hassan
Expert Review

Abstract

Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

KEY WORDS

opioid abuse opioid DDI opioid drug transporters opioids and P-gp 

ABBREVIATIONS

6-MAM

6-monoacetylmorphine

AAPCC

American Association for Poison Control Centers

AUC

Area under the curve

BBB

Blood–brain barrier

BCRP

Breast cancer resistance protein

CLin

Permeability clearance into the brain

CNS

Central nervous system

DDI

Drug-drug interaction

ED

Emergency department

FDA

Food and Drug Administration

GLUT

Glucose transporters

HEK293

Human embryonic kidney 293

IC50

Half maximal inhibitory concentration

Ki

Inhibition constant

Kp,uu

Ratio of unbound drug in the brain to unbound drug in the blood

M3G

Morphine-3-glucuronide

M6G

Morphine-6-glucuronide

MDMA

3,4-methylenedioxy-methamphetamine

MMT

Methadone maintenance treatment

MOR

μ-opioid receptor

MRP

Multidrug resistance-associated proteins

NSDUH

National Survey on Drug Use and Health

OAT

Organic anion transporters

OATP

Organic anion-transporting polypeptides

OCT

Organic cation transporters

PD

Pharmacodynamics

P-gp

P-glycoprotein

PK

Pharmacokinetics

Vu,brain

Volume of distribution within the brain

References

  1. 1.
    Steglitz J, Buscemi J, Ferguson MJ. The future of pain research, education, and treatment: a summary of the IOM report “Relieving pain in America: a blueprint for transforming prevention, care, education, and research”. Transl Behav Med. 2012;2:6–8.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Pizzoand PA, Clark NM. Alleviating suffering 101–pain relief in the United States. N Engl J Med. 2012;366:197–9.Google Scholar
  3. 3.
    Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;18:S3–13.PubMedGoogle Scholar
  4. 4.
    Mercerand SL, Coop A. Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance. Curr Top Med Chem. 2011;11:1157–64.Google Scholar
  5. 5.
    Beauchamp GA, Winstanley EL, Ryan SA, Lyons MS. Moving beyond misuse and diversion: the urgent need to consider the role of iatrogenic addiction in the current opioid epidemic. Am J Public Health. 2014;104:2023–9.Google Scholar
  6. 6.
    Fischer B, Keates A, Buhringer G, Reimer J, Rehm J. Non-medical use of prescription opioids and prescription opioid-related harms: why so markedly higher in North America compared to the rest of the world? Addiction. 2014;109:177–81.PubMedGoogle Scholar
  7. 7.
    Manchikanti L, Helm 2nd S, Fellows B, Janata JW, Pampati V, Grider JS, et al. Opioid epidemic in the United States. Pain Physician. 2012;15:ES9–38.PubMedGoogle Scholar
  8. 8.
    Gilson AM, Kreis PG. The burden of the nonmedical use of prescription opioid analgesics. Pain Med. 2009;10 Suppl 2:S89–100.PubMedGoogle Scholar
  9. 9.
    Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies–tackling the opioid-overdose epidemic. N Engl J Med. 2014;370:2063–6.PubMedGoogle Scholar
  10. 10.
    Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013;309:657–9.PubMedGoogle Scholar
  11. 11.
    N.I.o.D.A. (NIDA). Prescription Drug Abuse. 2014. Available from: http://www.drugabuse.gov/publications/research-reports/prescription-drugs/opioids. Accessed 22 Nov 2014.
  12. 12.
    S.A.M.H.S.A. (SAMHSA). Drug abuse warning network, 2011: national estimates of drug-related emergency department visits, HHS Publication No (SMA) 13–4760, DAWN Series D-39, vol. 2013. Rockville: Substance Abuse and Mental Health Services Administration; 2013.Google Scholar
  13. 13.
    Zhang L. Transporter-mediated Drug-Drug Interactions (DDIs). 2010. Available from: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/UCM207267.pdf. Accessed 22 Nov 2014.
  14. 14.
    Nagai N. Drug interaction studies on new drug applications: current situations and regulatory views in Japan. Drug Metab Pharmacokinet. 2010;25:3–15.Google Scholar
  15. 15.
    E.M.A. (EMA). Guideline on the investigation of drug interactions. 2012. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed 5 Mar 2015.
  16. 16.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry, drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. February 2012.Google Scholar
  17. 17.
    Hoand RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 2005;78:260–77.Google Scholar
  18. 18.
    Tanaka Y, Hipolito CJ, Maturana AD, Ito K, Kuroda T, Higuchi T, Katoh T, Kato HE, Hattori M, Kumazaki K, Tsukazaki T, Ishitani R, Suga H, Nureki O. Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. Nature. 2013;496:247–51.Google Scholar
  19. 19.
    Andre P, Debray M, Scherrmann JM, Cisternino S. Clonidine transport at the mouse blood–brain barrier by a new H+ antiporter that interacts with addictive drugs. J Cereb Blood Flow Metab. 2009;29:1293–304.PubMedGoogle Scholar
  20. 20.
    Cisternino S, Chapy H, Andre P, Smirnova M, Debray M, Scherrmann JM. Coexistence of passive and proton antiporter-mediated processes in nicotine transport at the mouse blood–brain barrier. AAPS J. 2013;15:299–307.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Vandenbossche J, Huisman M, Xu Y, Sanderson-Bongiovanni D, Soons P. Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance. J Pharm Pharmacol. 2010;62:401–12.PubMedGoogle Scholar
  22. 22.
    Hammarlund-Udenaes M, Friden M, Syvanen S, Gupta A. On the rate and extent of drug delivery to the brain. Pharm Res. 2008;25:1737–50.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Katzung BG, Masters SB, Trevor AJ. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill Medical; 2012.Google Scholar
  24. 24.
    Klimasand R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth. 2014;113:935–44.Google Scholar
  25. 25.
    De Gregori S, De Gregori M, Ranzani GN, Allegri M, Minella C, Regazzi M. Morphine metabolism, transport and brain disposition. Metab Brain Dis. 2012;27:1–5.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Wu D, Kang YS, Bickel U, Pardridge WM. Blood–brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. Drug Metab Dispos. 1997;25:768–71.PubMedGoogle Scholar
  27. 27.
    Bouw MR, Gardmark M, Hammarlund-Udenaes M. Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood–brain barrier as a cause of the antinociceptive effect delay in rats–a microdialysis study. Pharm Res. 2000;17:1220–7.PubMedGoogle Scholar
  28. 28.
    Tunblad K, Jonsson EN, Hammarlund-Udenaes M. Morphine blood–brain barrier transport is influenced by probenecid co-administration. Pharm Res. 2003;20:618–23.PubMedGoogle Scholar
  29. 29.
    F.a.D.A. (FDA). Prescribing Information: Morphine. 2009. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022195s002lbl.pdf. Accessed 5 Mar 2015.
  30. 30.
    Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;96:1698–705.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Letrent SP, Polli JW, Humphreys JE, Pollack GM, Brouwer KR, Brouwer KL. P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells. Biochem Pharmacol. 1999;58:951–7.PubMedGoogle Scholar
  32. 32.
    Callaghanand R, Riordan JR. Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J Biol Chem. 1993;268:16059–64.Google Scholar
  33. 33.
    Wandel C, Kim R, Wood M, Wood A. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology. 2002;96:913–20.PubMedGoogle Scholar
  34. 34.
    Crowe A. The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel. Eur J Pharmacol. 2002;440:7–16.PubMedGoogle Scholar
  35. 35.
    Huwyler J, Drewe J, Klusemann C, Fricker G. Evidence for P-glycoprotein-modulated penetration of morphine-6-glucuronide into brain capillary endothelium. Br J Pharmacol. 1996;118:1879–85.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Tournier N, Chevillard L, Megarbane B, Pirnay S, Scherrmann JM, Decleves X. Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). Int J Neuropsychopharmacol. 2010;13:905–15.PubMedGoogle Scholar
  37. 37.
    Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, et al. Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem. 2008;51:5932–42.PubMedGoogle Scholar
  38. 38.
    Tzvetkov MV, dos Santos Pereira JN, Meineke I, Saadatmand AR, Stingl JC, Brockmoller J. Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem Pharmacol. 2013;86:666–78.PubMedGoogle Scholar
  39. 39.
    van de Wetering K, Zelcer N, Kuil A, Feddema W, Hillebrand M, Vlaming ML, et al. Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides. Mol Pharmacol. 2007;72:387–94.PubMedGoogle Scholar
  40. 40.
    Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR, et al. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci U S A. 2005;102:7274–9.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC. The role of P-glycoprotein in blood–brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdr1a (+/+) mice. Br J Pharmacol. 1999;128:563–8.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Groenendaal D, Freijer J, de Mik D, Bouw MR, Danhof M, de Lange EC. Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux. Br J Pharmacol. 2007;151:701–12.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Tunblad K, Ederoth P, Gardenfors A, Hammarlund-Udenaes M, Nordstrom CH. Altered brain exposure of morphine in experimental meningitis studied with microdialysis. Acta Anaesthesiol Scand. 2004;48:294–301.PubMedGoogle Scholar
  44. 44.
    Bengtsson J, Bostrom E, Hammarlund-Udenaes M. The use of a deuterated calibrator for in vivo recovery estimations in microdialysis studies. J Pharm Sci. 2008;97:3433–41.PubMedGoogle Scholar
  45. 45.
    Bengtsson J, Ederoth P, Ley D, Hansson S, Amer-Wahlin I, Hellstrom-Westas L, et al. The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood–brain barrier in sheep. Br J Pharmacol. 2009;157:1085–96.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Letrent SP, Pollack GM, Brouwer KR, Brouwer KL. Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat. Pharm Res. 1998;15:599–605.PubMedGoogle Scholar
  47. 47.
    Aquilante CL, Letrent SP, Pollack GM, Brouwer KL. Increased brain P-glycoprotein in morphine tolerant rats. Life Sci. 2000;66:PL47–51.PubMedGoogle Scholar
  48. 48.
    Fujita-Hamabe W, Nishida M, Nawa A, Kobori T, Nakamoto K, Kishioka S, et al. Etoposide modulates the effects of oral morphine analgesia by targeting the intestinal P-glycoprotein. J Pharm Pharmacol. 2012;64:496–504.PubMedGoogle Scholar
  49. 49.
    Seleman M, Chapy H, Cisternino S, Courtin C, Smirnova M, Schlatter J, Chiadmi F, Scherrmann JM, Noble F, Marie-Claire C. Impact of P-glycoprotein at the blood–brain barrier on the uptake of heroin and its main metabolites: behavioral effects and consequences on the transcriptional responses and reinforcing properties. Psychopharmacology (Berl). 2014;231:3139–49.Google Scholar
  50. 50.
    Zongand J, Pollack GM. Morphine antinociception is enhanced in mdr1a gene-deficient mice. Pharm Res. 2000;17:749–53.Google Scholar
  51. 51.
    Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology. 2000;92:1392–9.PubMedGoogle Scholar
  52. 52.
    Dagenais C, Zong J, Ducharme J, Pollack GM. Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds. Pharm Res. 2001;18:957–63.PubMedGoogle Scholar
  53. 53.
    Hamabe W, Maeda T, Kiguchi N, Yamamoto C, Tokuyama S, Kishioka S. Negative relationship between morphine analgesia and P-glycoprotein expression levels in the brain. J Pharmacol Sci. 2007;105:353–60.PubMedGoogle Scholar
  54. 54.
    King M, Su W, Chang A, Zuckerman A, Pasternak GW. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat Neurosci. 2001;4:268–74.PubMedGoogle Scholar
  55. 55.
    Lotsch J, Schmidt R, Vetter G, Schmidt H, Niederberger E, Geisslinger G, et al. Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein. J Neurochem. 2002;83:241–8.PubMedGoogle Scholar
  56. 56.
    Bourasset F, Cisternino S, Temsamani J, Scherrmann JM. Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood–brain barrier. J Neurochem. 2003;86:1564–7.PubMedGoogle Scholar
  57. 57.
    Tunblad K, Hammarlund-Udenaes M, Jonsson EN. Influence of probenecid on the delivery of morphine-6-glucuronide to the brain. Eur J Pharm Sci. 2005;24:49–57.PubMedGoogle Scholar
  58. 58.
    Fudin J, Fontenelle DV, Payne A. Rifampin reduces oral morphine absorption: a case of transdermal buprenorphine selection based on morphine pharmacokinetics. J Pain Palliat Care Pharmacother. 2012;26:362–7.PubMedGoogle Scholar
  59. 59.
    Wang J, Cai B, Huang DX, Yang SD, Guo L. Decreased analgesic effect of morphine, but not buprenorphine, in patients with advanced P-glycoprotein(+) cancers. Pharmacol Rep. 2012;64:870–7.PubMedGoogle Scholar
  60. 60.
    Drewe J, Ball HA, Beglinger C, Peng B, Kemmler A, Schachinger H, et al. Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine. Br J Clin Pharmacol. 2000;50:237–46.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Meissner K, Avram MJ, Yermolenka V, Francis AM, Blood J, Kharasch ED. Cyclosporine-inhibitable blood–brain barrier drug transport influences clinical morphine pharmacodynamics. Anesthesiology. 2013;119:941–53.PubMedGoogle Scholar
  62. 62.
    Fujita K, Ando Y, Yamamoto W, Miya T, Endo H, Sunakawa Y, et al. Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer. Cancer Chemother Pharmacol. 2010;65:251–8.PubMedGoogle Scholar
  63. 63.
    Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008;83:559–66.PubMedGoogle Scholar
  64. 64.
    Coulbault L, Beaussier M, Verstuyft C, Weickmans H, Dubert L, Tregouet D, et al. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther. 2006;79:316–24.PubMedGoogle Scholar
  65. 65.
    Fukuda T, Chidambaran V, Mizuno T, Venkatasubramanian R, Ngamprasertwong P, Olbrecht V, et al. OCT1 genetic variants influence the pharmacokinetics of morphine in children. Pharmacogenomics. 2013;14:1141–51.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, et al. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002;300:918–24.PubMedGoogle Scholar
  67. 67.
    Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, et al. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009;50:1227–40.PubMedGoogle Scholar
  68. 68.
    Ahlin G, Chen L, Lazorova L, Chen Y, Ianculescu AG, Davis RL, et al. Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: predictions of metformin interactions. Pharmacogenomics J. 2011;11:400–11.PubMedGoogle Scholar
  69. 69.
    Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302:510–5.PubMedGoogle Scholar
  70. 70.
    Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol. 2003;63:844–8.PubMedGoogle Scholar
  71. 71.
    Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83:273–80.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117:1422–31.PubMedCentralPubMedGoogle Scholar
  73. 73.
    White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood. 2006;108:697–704.PubMedGoogle Scholar
  74. 74.
    Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A, et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006;66:8847–57.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Bourdet DL, Pritchard JB, Thakker DR. Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005;315:1288–97.PubMedGoogle Scholar
  76. 76.
    Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005;70:1851–60.PubMedGoogle Scholar
  77. 77.
    Amphoux A, Vialou V, Drescher E, Bruss M, Mannoury La Cour C, Rochat C, et al. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006;50:941–52.PubMedGoogle Scholar
  78. 78.
    Minematsu T, Iwai M, Umehara K, Usui T, Kamimura H. Characterization of human organic cation transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-mediated transport of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a novel small molecule survivin suppressant. Drug Metab Dispos. 2010;38:1–4.PubMedGoogle Scholar
  79. 79.
    Bachmakov I, Glaeser H, Fromm MF, Konig J. Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypeptides and organic cation transporter 1. Diabetes. 2008;57:1463–9.PubMedGoogle Scholar
  80. 80.
    Tzvetkov M, Saadatmand A, Lotsch J, Tegeder I, Stingl J, Brockmoller J. Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin Pharmacol Ther. 2011;90:143–50.PubMedGoogle Scholar
  81. 81.
    Polt R, Porreca F, Szabo LZ, Bilsky EJ, Davis P, Abbruscato TJ, et al. Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood–brain barrier. Proc Natl Acad Sci U S A. 1994;91:7114–8.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Yamada A, Maeda K, Kamiyama E, Sugiyama D, Kondo T, Shiroyanagi Y, et al. Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos. 2007;35:2166–76.PubMedGoogle Scholar
  83. 83.
    Yamashiro W, Maeda K, Hirouchi M, Adachi Y, Hu Z, Sugiyama Y. Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos. 2006;34:1247–54.PubMedGoogle Scholar
  84. 84.
    Guo A, Marinaro W, Hu P, Sinko PJ. Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002;30:457–63.PubMedGoogle Scholar
  85. 85.
    Chu XY, Kato Y, Ueda K, Suzuki H, Niinuma K, Tyson CA, et al. Biliary excretion mechanism of CPT-11 and its metabolites in humans: involvement of primary active transporters. Cancer Res. 1998;58:5137–43.PubMedGoogle Scholar
  86. 86.
    El-Sheikh AA, van den Heuvel JJ, Koenderink JB, Russel FG. Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J Pharmacol Exp Ther. 2007;320:229–35.PubMedGoogle Scholar
  87. 87.
    Tang F, Horie K, Borchardt RT. Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res. 2002;19:773–9.PubMedGoogle Scholar
  88. 88.
    Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE. Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. Drug Metab Dispos. 2007;35:340–4.PubMedGoogle Scholar
  89. 89.
    Matsushima S, Maeda K, Ishiguro N, Igarashi T, Sugiyama Y. Investigation of the inhibitory effects of various drugs on the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2008;36:663–9.PubMedGoogle Scholar
  90. 90.
    Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001;61:7225–32.PubMedGoogle Scholar
  91. 91.
    Busti AJ, Bain AM, Hall 2nd RG, Bedimo RG, Leff RD, Meek C, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol. 2008;51:605–10.PubMedGoogle Scholar
  92. 92.
    Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998;64:177–82.PubMedGoogle Scholar
  93. 93.
    Malingre MM, Richel DJ, Beijnen JH, Rosing H, Koopman FJ, Ten Bokkel Huinink WW, et al. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol. 2001;19:1160–6.PubMedGoogle Scholar
  94. 94.
    Meerum Terwogt JM, Malingre MM, Beijnen JH, ten Bokkel Huinink WW, Rosing H, Koopman FJ, et al. Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res. 1999;5:3379–84.PubMedGoogle Scholar
  95. 95.
    Kharasch ED, Hoffer C, Whittington D, Walker A, Bedynek PS. Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir. Anesthesiology. 2009;110:660–72.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Zheng HX, Huang Y, Frassetto LA, Benet LZ. Elucidating rifampin’s inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther. 2009;85:78–85.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Ding R, Tayrouz Y, Riedel KD, Burhenne J, Weiss J, Mikus G, et al. Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther. 2004;76:73–84.PubMedGoogle Scholar
  98. 98.
    Annaert P, Ye ZW, Stieger B, Augustijns P. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica. 2010;40:163–76.PubMedGoogle Scholar
  99. 99.
    Laskin OL, de Miranda P, King DH, Page DA, Longstreth JA, Rocco L, et al. Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans. Antimicrob Agents Chemother. 1982;21:804–7.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Cundy KC, Petty BG, Flaherty J, Fisher PE, Polis MA, Wachsman M, et al. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1995;39:1247–52.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Welling PG, Dean S, Selen A, Kendall MJ, Wise R. The pharmacokinetics of the oral cephalosporins cefaclor, cephradine and cephalexin. Int J Clin Pharmacol Biopharm. 1979;17:397–400.PubMedGoogle Scholar
  102. 102.
    Pitkin D, Dubb J, Actor P, Alexander F, Ehrlich S, Familiar R, et al. Kinetics and renal handling of cefonicid. Clin Pharmacol Ther. 1981;30:587–93.PubMedGoogle Scholar
  103. 103.
    Stoeckel K, Trueb V, Dubach UC, McNamara PJ. Effect of probenecid on the elimination and protein binding of ceftriaxone. Eur J Clin Pharmacol. 1988;34:151–6.PubMedGoogle Scholar
  104. 104.
    Jaehde U, Sorgel F, Reiter A, Sigl G, Naber KG, Schunack W. Effect of probenecid on the distribution and elimination of ciprofloxacin in humans. Clin Pharmacol Ther. 1995;58:532–41.PubMedGoogle Scholar
  105. 105.
    Liu S, Beringer PM, Hidayat L, Rao AP, Louie S, Burckart GJ, et al. Probenecid, but not cystic fibrosis, alters the total and renal clearance of fexofenadine. J Clin Pharmacol. 2008;48:957–65.PubMedGoogle Scholar
  106. 106.
    Inotsume N, Nishimura M, Nakano M, Fujiyama S, Sato T. The inhibitory effect of probenecid on renal excretion of famotidine in young, healthy volunteers. J Clin Pharmacol. 1990;30:50–6.PubMedGoogle Scholar
  107. 107.
    Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CP. Probenecid inhibits the renal clearance of frusemide and its acyl glucuronide. Br J Clin Pharmacol. 1995;39:692–5.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Shiveley L, Struthers-Semple C, Cox S, Sawyer J. Pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in healthy volunteers treated with trimethoprim-sulphamethoxazole. J Clin Pharm Ther. 2008;33:45–54.PubMedGoogle Scholar
  109. 109.
    Fischer W, Bernhagen J, Neubert RH, Brandsch M. Uptake of codeine into intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells. Eur J Pharm Sci. 2010;41:31–42.PubMedGoogle Scholar
  110. 110.
    Hassan HE, Myers AL, Lee IJ, Coop A, Eddington ND. Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel’s tissue distribution in Sprague Dawley rats. J Pharm Sci. 2007;96:2494–506.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Hassan HE, Mercer SL, Cunningham CW, Coop A, Eddington ND. Evaluation of the P-glycoprotein (Abcb1) affinity status of a series of morphine analogs: comparative study with meperidine analogs to identify opioids with minimal P-glycoprotein interactions. Int J Pharm. 2009;375:48–54.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Bostrom E, Simonsson US, Hammarlund-Udenaes M. In vivo blood–brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics. Drug Metab Dispos. 2006;34:1624–31.PubMedGoogle Scholar
  113. 113.
    Zwisler ST, Enggaard TP, Noehr-Jensen L, Mikkelsen S, Verstuyft C, Becquemont L, et al. The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes. Fundam Clin Pharmacol. 2010;24:517–24.PubMedGoogle Scholar
  114. 114.
    Lam J, Kelly L, Matok I, Ross CJ, Carleton BC, Hayden MR, et al. Putative association of ABCB1 2677G>T/A with oxycodone-induced central nervous system depression in breastfeeding mothers. Ther Drug Monit. 2013;35:466–72.PubMedGoogle Scholar
  115. 115.
    Naito T, Takashina Y, Yamamoto K, Tashiro M, Ohnishi K, Kagawa Y, et al. CYP3A5*3 affects plasma disposition of noroxycodone and dose escalation in cancer patients receiving oxycodone. J Clin Pharmacol. 2011;51:1529–38.PubMedGoogle Scholar
  116. 116.
    Olkkola KT, Kontinen VK, Saari TI, Kalso EA. Does the pharmacology of oxycodone justify its increasing use as an analgesic? Trends Pharmacol Sci. 2013;34:206–14.PubMedGoogle Scholar
  117. 117.
    Hassan HE, Myers AL, Lee IJ, Chen H, Coop A, Eddington ND. Regulation of gene expression in brain tissues of rats repeatedly treated by the highly abused opioid agonist, oxycodone: microarray profiling and gene mapping analysis. Drug Metab Dispos. 2010;38:157–67.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Ni Z, Bikadi Z, Rosenberg MF, Mao Q. Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab. 2010;11:603–17.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Holland ML, Lau DT, Allen JD, Arnold JC. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids. Br J Pharmacol. 2007;152:815–24.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Spiro AS, Wong A, Boucher AA, Arnold JC. Enhanced brain disposition and effects of Delta9-tetrahydrocannabinol in P-glycoprotein and breast cancer resistance protein knockout mice. PLoS One. 2012;7:e35937.PubMedCentralPubMedGoogle Scholar
  121. 121.
    Okura T, Hattori A, Takano Y, Sato T, Hammarlund-Udenaes M, Terasaki T, et al. Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood–brain barrier transport of oxycodone. Drug Metab Dispos. 2008;36:2005–13.PubMedGoogle Scholar
  122. 122.
    Nakazawa Y, Okura T, Shimomura K, Terasaki T, Deguchi Y. Drug-drug interaction between oxycodone and adjuvant analgesics in blood–brain barrier transport and antinociceptive effect. J Pharm Sci. 2010;99:467–74.PubMedGoogle Scholar
  123. 123.
    Sadiq MW, Borgs A, Okura T, Shimomura K, Kato S, Deguchi Y, et al. Diphenhydramine active uptake at the blood–brain barrier and its interaction with oxycodone in vitro and in vivo. J Pharm Sci. 2011;100:3912–23.PubMedGoogle Scholar
  124. 124.
    Shimomura K, Okura T, Kato S, Couraud PO, Schermann JM, Terasaki T, et al. Functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, a human blood–brain barrier model. Fluids Barriers CNS. 2013;10:8.PubMedCentralPubMedGoogle Scholar
  125. 125.
    Sadiq MW, Bostrom E, Keizer R, Bjorkman S, Hammarlund-Udenaes M. Oxymorphone active uptake at the blood–brain barrier and population modeling of its pharmacokinetic-pharmacodynamic relationship. J Pharm Sci. 2013;102:3320–31.PubMedGoogle Scholar
  126. 126.
    Henthorn TK, Liu Y, Mahapatro M, Ng KY. Active transport of fentanyl by the blood–brain barrier. J Pharmacol Exp Ther. 1999;289:1084–9.PubMedGoogle Scholar
  127. 127.
    Hamabe W, Maeda T, Fukazawa Y, Kumamoto K, Shang LQ, Yamamoto A, et al. P-glycoprotein ATPase activating effect of opioid analgesics and their P-glycoprotein-dependent antinociception in mice. Pharmacol Biochem Behav. 2006;85:629–36.PubMedGoogle Scholar
  128. 128.
    Cirella VN, Pantuck CB, Lee YJ, Pantuck EJ. Effects of cyclosporine on anesthetic action. Anesth Analg. 1987;66:703–6.PubMedGoogle Scholar
  129. 129.
    Mayer U, Wagenaar E, Dorobek B, Beijnen JH, Borst P, Schinkel AH. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood–brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest. 1997;100:2430–6.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Dagenais C, Graff CL, Pollack GM. Variable modulation of opioid brain uptake by P-glycoprotein in mice. Biochem Pharmacol. 2004;67:269–76.PubMedGoogle Scholar
  131. 131.
    Kharasch ED, Hoffer C, Altuntas TG, Whittington D. Quinidine as a probe for the role of p-glycoprotein in the intestinal absorption and clinical effects of fentanyl. J Clin Pharmacol. 2004;44:224–33.PubMedGoogle Scholar
  132. 132.
    Park HJ, Shinn HK, Ryu SH, Lee HS, Park CS, Kang JH. Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin Pharmacol Ther. 2007;81:539–46.PubMedGoogle Scholar
  133. 133.
    Kesimci E, Engin AB, Kanbak O, Karahalil B. Association between ABCB1 gene polymorphisms and fentanyl’s adverse effects in Turkish patients undergoing spinal anesthesia. Gene. 2012;493:273–7.PubMedGoogle Scholar
  134. 134.
    Skrobik Y, Leger C, Cossette M, Michaud V, Turgeon J. Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors. Crit Care Med. 2013;41:999–1008.PubMedGoogle Scholar
  135. 135.
    Ziesenitz VC, Konig SK, Mahlke N, Jantos R, Skopp G, Weiss J, et al. Fentanyl pharmacokinetics is not dependent on hepatic uptake by organic anion-transporting polypeptide 1B1 in human beings. Basic Clin Pharmacol Toxicol. 2013;113:43–8.PubMedGoogle Scholar
  136. 136.
    Elkiweri IA, Zhang YL, Christians U, Ng KY, Tissot van Patot MC, Henthorn TK. Competitive substrates for P-glycoprotein and organic anion protein transporters differentially reduce blood organ transport of fentanyl and loperamide: pharmacokinetics and pharmacodynamics in Sprague–Dawley rats. Anesth Analg. 2009;108:149–59.PubMedCentralPubMedGoogle Scholar
  137. 137.
    Bouer R, Barthe L, Philibert C, Tournaire C, Woodley J, Houin G. The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac. Fundam Clin Pharmacol. 1999;13:494–500.PubMedGoogle Scholar
  138. 138.
    Stormer E, Perloff MD, von Moltke LL, Greenblatt DJ. Methadone inhibits rhodamine123 transport in Caco-2 cells. Drug Metab Dispos. 2001;29:954–6.PubMedGoogle Scholar
  139. 139.
    Beghin D, Delongeas JL, Claude N, Farinotti R, Forestier F, Gil S. Comparative effects of drugs on P-glycoprotein expression and activity using rat and human trophoblast models. Toxicol In Vitro. 2010;24:630–7.PubMedGoogle Scholar
  140. 140.
    Crettol S, Digon P, Golay KP, Brawand M, Eap CB. In vitro P-glycoprotein-mediated transport of (R)-, (S)-, (R, S)-methadone, LAAM and their main metabolites. Pharmacology. 2007;80:304–11.PubMedGoogle Scholar
  141. 141.
    Nanovskaya T, Nekhayeva I, Karunaratne N, Audus K, Hankins GD, Ahmed MS. Role of P-glycoprotein in transplacental transfer of methadone. Biochem Pharmacol. 2005;69:1869–78.PubMedCentralPubMedGoogle Scholar
  142. 142.
    Nekhayeva IA, Nanovskaya TN, Deshmukh SV, Zharikova OL, Hankins GD, Ahmed MS. Bidirectional transfer of methadone across human placenta. Biochem Pharmacol. 2005;69:187–97.PubMedGoogle Scholar
  143. 143.
    Hemauer SJ, Patrikeeva SL, Nanovskaya TN, Hankins GD, Ahmed MS. Opiates inhibit paclitaxel uptake by P-glycoprotein in preparations of human placental inside-out vesicles. Biochem Pharmacol. 2009;78:1272–8.PubMedCentralPubMedGoogle Scholar
  144. 144.
    Linardi RL, Stokes AM, Andrews FM. The effect of P-glycoprotein on methadone hydrochloride flux in equine intestinal mucosa. J Vet Pharmacol Ther. 2013;36:43–50.PubMedGoogle Scholar
  145. 145.
    Hung CC, Chiou MH, Teng YN, Hsieh YW, Huang CL, Lane HY. Functional impact of ABCB1 variants on interactions between P-glycoprotein and methadone. PLoS One. 2013;8:e59419.PubMedCentralPubMedGoogle Scholar
  146. 146.
    Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL. Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood–brain barrier of Abcb1a gene knockout mice. Psychopharmacology (Berl). 2004;173:132–8.Google Scholar
  147. 147.
    Rodriguez M, Ortega I, Soengas I, Suarez E, Lukas JC, Calvo R. Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution in the rat. J Pharm Pharmacol. 2004;56:367–74.PubMedGoogle Scholar
  148. 148.
    Ortega I, Rodriguez M, Suarez E, Perez-Ruixo JJ, Calvo R. Modeling methadone pharmacokinetics in rats in presence of P-glycoprotein inhibitor valspodar. Pharm Res. 2007;24:1299–308.PubMedGoogle Scholar
  149. 149.
    Kreek MJ, Garfield JW, Gutjahr CL, Giusti LM. Rifampin-induced methadone withdrawal. N Engl J Med. 1976;294:1104–6.PubMedGoogle Scholar
  150. 150.
    Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet. 2003;42:819–50.PubMedGoogle Scholar
  151. 151.
    Eich-Hochli D, Oppliger R, Golay KP, Baumann P, Eap CB. Methadone maintenance treatment and St. John’s Wort—a case report. Pharmacopsychiatry. 2003;36:35–7.PubMedGoogle Scholar
  152. 152.
    Kharasch ED, Bedynek PS, Hoffer C, Walker A, Whittington D. Lack of indinavir effects on methadone disposition despite inhibition of hepatic and intestinal cytochrome P4503A (CYP3A). Anesthesiology. 2012;116:432–47.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Kharasch ED, Bedynek PS, Walker A, Whittington D, Hoffer C. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities. Clin Pharmacol Ther. 2008;84:506–12.PubMedCentralPubMedGoogle Scholar
  154. 154.
    Kharaschand ED, Stubbert K. Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir. Drug Metab Dispos. 2013;41:2166–74.Google Scholar
  155. 155.
    Coller JK, Barratt DT, Dahlen K, Loennechen MH, Somogyi AA. ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther. 2006;80:682–90.PubMedGoogle Scholar
  156. 156.
    Levran O, O’Hara K, Peles E, Li D, Barral S, Ray B, et al. ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet. 2008;17:2219–27.PubMedCentralPubMedGoogle Scholar
  157. 157.
    Hung CC, Chiou MH, Huang BH, Hsieh YW, Hsieh TJ, Huang CL, et al. Impact of genetic polymorphisms in ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genes on methadone therapy in Han Chinese patients. Pharmacogenomics. 2011;12:1525–33.PubMedGoogle Scholar
  158. 158.
    Uehlinger C, Crettol S, Chassot P, Brocard M, Koeb L, Brawand-Amey M, et al. Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients. J Clin Psychopharmacol. 2007;27:273–8.PubMedGoogle Scholar
  159. 159.
    Lee HY, Li JH, Sheu YL, Tang HP, Chang WC, Tang TC, et al. Moving toward personalized medicine in the methadone maintenance treatment program: a pilot study on the evaluation of treatment responses in Taiwan. Biomed Res Int. 2013;2013:741403.PubMedCentralPubMedGoogle Scholar
  160. 160.
    Barratt DT, Coller JK, Hallinan R, Byrne A, White JM, Foster DJ, et al. ABCB1 haplotype and OPRM1 118A>G genotype interaction in methadone maintenance treatment pharmacogenetics. Curr Pharmgenomics Pers Med. 2012;5:53–62.Google Scholar
  161. 161.
    Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, Hammig R, Gothuey I, et al. No influence of ABCB1 haplotypes on methadone dosage requirement. Clin Pharmacol Ther. 2008;83:668–9. author reply 669–670.PubMedGoogle Scholar
  162. 162.
    Fonseca F, de la Torre R, Diaz L, Pastor A, Cuyas E, Pizarro N, et al. Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. PLoS One. 2011;6. e19527.Google Scholar
  163. 163.
    Lotsch J, Skarke C, Wieting J, Oertel BG, Schmidt H, Brockmoller J, et al. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther. 2006;79:72–89.PubMedGoogle Scholar
  164. 164.
    Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, Hammig R, Gothuey I, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther. 2006;80:668–81.PubMedGoogle Scholar
  165. 165.
    Buchard A, Linnet K, Johansen SS, Munkholm J, Fregerslev M, Morling N. Postmortem blood concentrations of R- and S-enantiomers of methadone and EDDP in drug users: influence of co-medication and p-glycoprotein genotype. J Forensic Sci. 2010;55:457–63.PubMedGoogle Scholar
  166. 166.
    Brown SM, Campbell SD, Crafford A, Regina KJ, Holtzman MJ, Kharasch ED. P-glycoprotein is a major determinant of norbuprenorphine brain exposure and antinociception. J Pharmacol Exp Ther. 2012;343:53–61.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Nekhayeva IA, Nanovskaya TN, Hankins GD, Ahmed MS. Role of human placental efflux transporter P-glycoprotein in the transfer of buprenorphine, levo-alpha-acetylmethadol, and paclitaxel. Am J Perinatol. 2006;23:423–30.PubMedGoogle Scholar
  168. 168.
    Suzuki T, Zaima C, Moriki Y, Fukami T, Tomono K. P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier. J Drug Target. 2007;15:67–74.PubMedGoogle Scholar
  169. 169.
    Alhaddad H, Cisternino S, Decleves X, Tournier N, Schlatter J, Chiadmi F, et al. Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice. Crit Care Med. 2012;40:3215–23.PubMedGoogle Scholar
  170. 170.
    Megarbaneand B, Alhaddad H. Can P-glycoprotein expression on malignant tumor tissues predict opioid transport at the blood–brain barrier in cancer patients? Pharmacol Rep. 2013;65:235–6.Google Scholar
  171. 171.
    Kanaan M, Daali Y, Dayer P, Desmeules J. Uptake/efflux transport of tramadol enantiomers and O-desmethyl-tramadol: focus on P-glycoprotein. Basic Clin Pharmacol Toxicol. 2009;105:199–206.PubMedCentralPubMedGoogle Scholar
  172. 172.
    Sheikholeslami B, Hamidi M, Lavasani H, Sharifzadeh M, Rouini M. Lack of evidence for involvement of P-glycoprotein in brain uptake of the centrally acting analgesic, tramadol in the rat. J Pharm Pharm Sci. 2012;15:606–15.PubMedGoogle Scholar
  173. 173.
    Slanar O, Nobilis M, Kvetina J, Matsoukova O, Idle J, Perlik F. Pharmacokinetics of tramadol is affected by MDR1 polymorphism C3435T. Eur J Clin Pharmacol. 2007;63:419–21.PubMedGoogle Scholar
  174. 174.
    Slanar O, Dupal P, Matsoukova O, Vondrackova H, Pafko P, Perlik F. Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms. Bratisl Lek Listy. 2012;113:152–5.PubMedGoogle Scholar
  175. 175.
    Hagelberg N, Saarikoski T, Saari T, Neuvonen M, Neuvonen P, Turpeinen M, et al. Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol inte. Eur J Clin Pharmacol. 2013;69:867–75.PubMedGoogle Scholar
  176. 176.
    Kitamura A, Higuchi K, Okura T, Deguchi Y. Transport characteristics of tramadol in the blood–brain barrier. J Pharm Sci. 2014;103:3335–41.PubMedGoogle Scholar
  177. 177.
    Zhang L, Schaner ME, Giacomini KM. Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther. 1998;286:354–61.PubMedGoogle Scholar
  178. 178.
    Bolserand DC, Davenport PW. Codeine and cough: an ineffective gold standard. Curr Opin Allergy Clin Immunol. 2007;7:32–6.Google Scholar
  179. 179.
    Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol. 1991;31:381–90.PubMedCentralPubMedGoogle Scholar
  180. 180.
    Xieand R, Hammarlund-Udenaes M. Blood–brain barrier equilibration of codeine in rats studied with microdialysis. Pharm Res. 1998;15:570–5.Google Scholar
  181. 181.
    I.I.f.H. Informatics. The use of medicines in the United States: review of 2011. 2012. Available from: http://www.imshealth.com/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/IHII_Medicines_in_U.S_Report_2011.pdf. Accessed 22 Nov 2014.
  182. 182.
    Findlay JW, Jones EC, Butz RF, Welch RM. Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics. Clin Pharmacol Ther. 1978;24:60–8.PubMedGoogle Scholar
  183. 183.
    Murphy LS, Oros MT, Dorsey SG. The Baltimore buprenorphine initiative: understanding the role of buprenorphine in addressing heroin addiction in an urban-based community. J Addict Nurs. 2014;25:16–25. quiz 26–17.PubMedGoogle Scholar
  184. 184.
    U.N.O.o.D.a.C. (UNODC). World drug report 2013. 2011. Available from: https://www.unodc.org/documents/data-and-analysis/tocta/5.Heroin.pdf. Accessed 22 Nov 2014.
  185. 185.
    Gottas A, Oiestad EL, Boix F, Vindenes V, Ripel A, Thaulow CH, et al. Levels of heroin and its metabolites in blood and brain extracellular fluid after i.v. heroin administration to freely moving rats. Br J Pharmacol. 2013;170:546–56.PubMedCentralPubMedGoogle Scholar
  186. 186.
    Oldendorf WH, Hyman S, Braun L, Oldendorf SZ. Blood–brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science. 1972;178:984–6.PubMedGoogle Scholar
  187. 187.
    Gottas A, Oiestad EL, Boix F, Ripel A, Thaulow CH, Pettersen BS, et al. Simultaneous measurement of heroin and its metabolites in brain extracellular fluid by microdialysis and ultra performance liquid chromatography tandem mass spectrometry. J Pharmacol Toxicol Methods. 2012;66:14–21.PubMedGoogle Scholar
  188. 188.
    Hutchinsonand MR, Somogyi AA. Diacetylmorphine degradation to 6-monoacetylmorphine and morphine in cell culture: implications for in vitro studies. Eur J Pharmacol. 2002;453:27–32.Google Scholar
  189. 189.
    Rook EJ, Huitema AD, van den Brink W, van Ree JM, Beijnen JH. Population pharmacokinetics of heroin and its major metabolites. Clin Pharmacokinet. 2006;45:401–17.PubMedGoogle Scholar
  190. 190.
    S.A.a.M.H.S.A. (SAMHSA). Results from the 2012 national survey on drug use and health: summary of national findings, NSDUH Series H-46, HHS Publication No (SMA) 13–479, Vol. NSDUH Series H-46. Rockville: Substance Abuse and Mental Health Services Administration; 2013.Google Scholar
  191. 191.
    N.I.o.D.A. (NIDA). Drug facts: heroin. 2014. [cited 2014 Oct 26]. Available from: http://www.drugabuse.gov/publications/drugfacts/heroin.
  192. 192.
    Loh HH, Shen FH, Way EL. Effect of dactinomycin on the acute toxicity and brain uptake of morphine. J Pharmacol Exp Ther. 1971;177:326–31.PubMedGoogle Scholar
  193. 193.
    Andersen JM, Ripel A, Boix F, Normann PT, Morland J. Increased locomotor activity induced by heroin in mice: pharmacokinetic demonstration of heroin acting as a prodrug for the mediator 6-monoacetylmorphine in vivo. J Pharmacol Exp Ther. 2009;331:153–61.PubMedGoogle Scholar
  194. 194.
    Gottas A, Boix F, Oiestad EL, Vindenes V, Morland J. Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin. Int J Neuropsychopharmacol. 2014;17:1357-65.Google Scholar
  195. 195.
    D.E.A. (DEA). Oxycodone. 2014. Available from:http://www.deadiversion.usdoj.gov/drug_chem_info/oxycodone/oxycodone.pdf. Accessed 15 Jun 2014.
  196. 196.
    Wightman R, Perrone J, Portelli I, Nelson L. Likeability and abuse liability of commonly prescribed opioids. J Med Toxicol. 2012;8:335–40.PubMedCentralPubMedGoogle Scholar
  197. 197.
    Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther. 2006;79:461–79.PubMedGoogle Scholar
  198. 198.
    United States Department of Health and Human Services. Substance Abuse and Mental Health Services Administration. Office of Applied Studies. National Survey on Drug Use and Health, 2006. ICPSR21240-v6. Ann Arbor, MI: Inter-university Consortium for Political and Social Research [distributor], 2013-06-21. doi:10.3886/ICPSR21240.v6.
  199. 199.
    Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, et al. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther. 2002;303:1029–37.PubMedGoogle Scholar
  200. 200.
    Kuwayama K, Inoue H, Kanamori T, Tsujikawa K, Miyaguchi H, Iwata Y, et al. Uptake of 3,4-methylenedioxymethamphetamine and its related compounds by a proton-coupled transport system in Caco-2 cells. Biochim Biophys Acta. 2008;1778:42–50.PubMedGoogle Scholar
  201. 201.
    Villesen HH, Foster DJ, Upton RN, Somogyi AA, Martinez A, Grant C. Cerebral kinetics of oxycodone in conscious sheep. J Pharm Sci. 2006;95:1666–76.PubMedGoogle Scholar
  202. 202.
    Bostrom E, Simonsson US, Hammarlund-Udenaes M. Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J Pharm Sci. 2005;94:1060–6.PubMedGoogle Scholar
  203. 203.
    D.E.A. (DEA). Oxymorphone. 2013. Available from:http://www.deadiversion.usdoj.gov/drug_chem_info/oxymorphone.pdf. Accessed 26 Oct 2014.
  204. 204.
    Peckhamand EM, Traynor JR. Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague–Dawley rats. J Pharmacol Exp Ther. 2006;316:1195–201.Google Scholar
  205. 205.
    Beaver WT, Wallenstein SL, Houde RW, Rogers A. Comparisons of the analgesic effects of oral and intramuscular oxymorphone and of intramuscular oxymorphone and morphine in patients with cancer. J Clin Pharmacol. 1977;17:186–98.PubMedGoogle Scholar
  206. 206.
    Ananthan S, Khare NK, Saini SK, Seitz LE, Bartlett JL, Davis P, et al. Identification of opioid ligands possessing mixed micro agonist/delta antagonist activity among pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone [correction of hydropmorphone]. J Med Chem. 2004;47:1400–12.PubMedGoogle Scholar
  207. 207.
    Pengand PW, Sandler AN. A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology. 1999;90:576–99.Google Scholar
  208. 208.
    D.E.A. (DEA). Fentanyl. 2014. Available from: http://www.deadiversion.usdoj.gov/drug_chem_info/fentanyl.pdf. Accessed 8 Jun 2014.
  209. 209.
    Waters CM, Avram MJ, Krejcie TC, Henthorn TK. Uptake of fentanyl in pulmonary endothelium. J Pharmacol Exp Ther. 1999;288:157–63.PubMedGoogle Scholar
  210. 210.
    Tetrault JM, Kozal MJ, Chiarella J, Sullivan LE, Dinh AT, Fiellin DA. Association between risk behaviors and antiretroviral resistance in HIV-infected patients receiving opioid agonist treatment. J Addict Med. 2013;7:102–7.PubMedCentralPubMedGoogle Scholar
  211. 211.
    D.E.A. (DEA). Methadone. 2014. Available from: http://www.deadiversion.usdoj.gov/drug_chem_info/methadone/methadone.pdf. Accessed 8 Jun 2014.
  212. 212.
    Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev. 2007;1:1-23.Google Scholar
  213. 213.
    Rainey PM, Friedland GH, Snidow JW, McCance-Katz EF, Mitchell SM, Andrews L, et al. The pharmacokinetics of methadone following co-administration with a lamivudine/zidovudine combination tablet in opiate-dependent subjects. Am J Addict. 2002;11:66–74.PubMedGoogle Scholar
  214. 214.
    Kreek MJ, Borg L, Ducat E, Ray B. Pharmacotherapy in the treatment of addiction: methadone. J Addict Dis. 2010;29:200–16.PubMedCentralPubMedGoogle Scholar
  215. 215.
    Armstrong SC, Wynn GH, Sandson NB. Pharmacokinetic drug interactions of synthetic opiate analgesics. Psychosomatics. 2009;50:169–76.PubMedGoogle Scholar
  216. 216.
    McCance-Katzand EF, Mandell TW. Drug interactions of clinical importance with methadone and buprenorphine. Am J Addict. 2010;19:2–3.Google Scholar
  217. 217.
    Justo D. Methadone-induced long QT syndrome vs methadone-induced torsades de pointes. Arch Intern Med. 2006;166:2288. author reply 2289–2290.PubMedGoogle Scholar
  218. 218.
    Ehret GB, Desmeules JA, Broers B. Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology. Expert Opin Drug Saf. 2007;6:289–303.PubMedGoogle Scholar
  219. 219.
    Bronstein AC, Spyker DA, Cantilena Jr LR, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012;50:911–1164.Google Scholar
  220. 220.
    Bauer B, Yang X, Hartz AM, Olson ER, Zhao R, Kalvass JC, et al. In vivo activation of human pregnane X receptor tightens the blood–brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol. 2006;70:1212–9.PubMedGoogle Scholar
  221. 221.
    Kukanich B, Lascelles BD, Aman AM, Mealey KL, Papich MG. The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs. J Vet Pharmacol Ther. 2005;28:461–6.PubMedGoogle Scholar
  222. 222.
    Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004;75:13–33.PubMedGoogle Scholar
  223. 223.
    Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70:189–99.PubMedGoogle Scholar
  224. 224.
    Takane H, Kobayashi D, Hirota T, Kigawa J, Terakawa N, Otsubo K, et al. Haplotype-oriented genetic analysis and functional assessment of promoter variants in the MDR1 (ABCB1) gene. J Pharmacol Exp Ther. 2004;311:1179–87.PubMedGoogle Scholar
  225. 225.
    Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics. 2003;13:481–94.PubMedGoogle Scholar
  226. 226.
    Gowing L, Ali R, White JM. Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev. 2009;4:1–45.Google Scholar
  227. 227.
    Brown SM, Holtzman M, Kim T, Kharasch ED. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology. 2011;115:1251–60.PubMedCentralPubMedGoogle Scholar
  228. 228.
    D.E.A. (DEA). Buprenorphine. 2013. Available from: http://www.deadiversion.usdoj.gov/drug_chem_info/buprenorphine.pdf. Accessed 8 Jun 2014.
  229. 229.
    Guo AY, Ma JD, Best BM, Atayee RS. Urine specimen detection of concurrent nonprescribed medicinal and illicit drug use in patients prescribed buprenorphine. J Anal Toxicol. 2013;37:636–41.PubMedGoogle Scholar
  230. 230.
    Cowan A, Lewis JW, Macfarlane IR. Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol. 1977;60:537–45.PubMedCentralPubMedGoogle Scholar
  231. 231.
    Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569–80.PubMedGoogle Scholar
  232. 232.
    Moody DE, Slawson MH, Strain EC, Laycock JD, Spanbauer AC, Foltz RL. A liquid chromatographic-electrospray ionization-tandem mass spectrometric method for determination of buprenorphine, its metabolite, norbuprenorphine, and a coformulant, naloxone, that is suitable for in vivo and in vitro metabolism studies. Anal Biochem. 2002;306:31–9.PubMedGoogle Scholar
  233. 233.
    Huang P, Kehner GB, Cowan A, Liu-Chen LY. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther. 2001;297:688–95.PubMedGoogle Scholar
  234. 234.
    Ohtani M, Kotaki H, Nishitateno K, Sawada Y, Iga T. Kinetics of respiratory depression in rats induced by buprenorphine and its metabolite, norbuprenorphine. J Pharmacol Exp Ther. 1997;281:428–33.PubMedGoogle Scholar
  235. 235.
    Alhaddad H, Cisternino S, Saubamea B, Schlatter J, Chiadmi F, Risede P, et al. Gender and strain contributions to the variability of buprenorphine-related respiratory toxicity in mice. Toxicology. 2013;305:99–108.PubMedGoogle Scholar
  236. 236.
    McCance-Katz EF, Rainey PM, Moody DE. Effect of cocaine use on buprenorphine pharmacokinetics in humans. Am J Addict. 2010;19:38–46.PubMedGoogle Scholar
  237. 237.
    Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int. 2001;121:65–9.PubMedGoogle Scholar
  238. 238.
    Lai SH, Yao YJ, Lo DS. A survey of buprenorphine related deaths in Singapore. Forensic Sci Int. 2006;162:80–6.PubMedGoogle Scholar
  239. 239.
    Selden T, Ahlner J, Druid H, Kronstrand R. Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome. Forensic Sci Int. 2012;220:284–90.PubMedGoogle Scholar
  240. 240.
    D.E.A. (DEA). Tramadol. 2013. Available from: http://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Accessed 22 Nov 2014.
  241. 241.
    D.E.A. (DEA). Hydrocodone. 2014. Available from: http://www.deadiversion.usdoj.gov/drug_chem_info/hydrocodone.pdf. Accessed 6 Jun 2014.
  242. 242.
    Overholser BR, Foster DR. Opioid pharmacokinetic drug-drug interactions. Am J Manag Care. 2011;17:S276–87.Google Scholar
  243. 243.
    Kaplan HL, Busto UE, Baylon GJ, Cheung SW, Otton SV, Somer G, et al. Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther. 1997;281:103–8.PubMedGoogle Scholar
  244. 244.
    Tomkins DM, Otton SV, Joharchi N, Li NY, Balster RF, Tyndale RF, et al. Effect of cytochrome P450 2D1 inhibition on hydrocodone metabolism and its behavioral consequences in rats. J Pharmacol Exp Ther. 1997;280:1374–82.PubMedGoogle Scholar
  245. 245.
    D.E.A. (DEA). Hydromorphone. 2013. Available from: http://www.deadiversion.usdoj.gov/drug_chem_info/hydromorphone.pdf. Accessed 6 Jun 2014.
  246. 246.
    Muecklerand M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med. 2013;34:121–38.Google Scholar
  247. 247.
    Munoz M, Henderson M, Haber M, Norris M. Role of the MRP1/ABCC1 multidrug transporter protein in cancer. IUBMB Life. 2007;59:752–7.PubMedGoogle Scholar
  248. 248.
    Zochbauer-Muller S, Filipits M, Rudas M, Brunner R, Krajnik G, Suchomel R, et al. P-glycoprotein and MRP1 expression in axillary lymph node metastases of breast cancer patients. Anticancer Res. 2001;21:119–24.PubMedGoogle Scholar
  249. 249.
    Filipits M, Malayeri R, Suchomel RW, Pohl G, Stranzl T, Dekan G, et al. Expression of the multidrug resistance protein (MRP1) in breast cancer. Anticancer Res. 1999;19:5043–9.PubMedGoogle Scholar
  250. 250.
    Natarajan K, Xie Y, Baer MR, Ross DD. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol. 2012;83:1084–103.PubMedCentralPubMedGoogle Scholar
  251. 251.
    Sasu-Tenkoramaa J, Fudin J. Drug interactions in cancer patients requiring concomitant chemotherapy and analgesics. Pract Pain Manag. 2013;50–60.Google Scholar
  252. 252.
    Nakanishi T. Drug transporters as targets for cancer chemotherapy. Cancer Genomics Proteomics. 2007;4:241–54.PubMedGoogle Scholar
  253. 253.
    Nakanishiand T, Tamai I. Solute carrier transporters as targets for drug delivery and pharmacological intervention for chemotherapy. J Pharm Sci. 100:3731–50.Google Scholar
  254. 254.
    Albermann N, Schmitz-Winnenthal FH, Z’Graggen K, Volk C, Hoffmann MM, Haefeli WE, et al. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol. 2005;70:949–58.PubMedGoogle Scholar
  255. 255.
    Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, Zhang L. Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther. 94:52–63.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Robert Gharavi
    • 1
    • 2
  • William Hedrich
    • 1
  • Hongbing Wang
    • 1
  • Hazem E. Hassan
    • 1
    • 3
  1. 1.Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreUSA
  2. 2.Clinical DevelopmentMedImmuneGaithersburgUSA
  3. 3.Department of Pharmaceutics and Industrial Pharmacy, Faculty of PharmacyHelwan UniversityCairoEgypt

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