Mechanisms of Drug Interactions I: Absorption, Metabolism, and Excretion

  • David M. Burger
  • Lindsey H. M. te Brake
  • Rob E. Aarnoutse
Part of the Infectious Disease book series (ID)


Understanding the basic mechanisms of drug interactions allows researchers and clinicians to best interpret and apply drug interaction data and make predictions about patient-specific interactions. Drug interactions can occur during the absorption, distribution, metabolism, and excretion phases of drug distribution (pharmacokinetic interactions) and at the site of action (pharmacodynamic interactions). The consequences of unintended interactions can be extremely harmful and potentially fatal, such as those leading to cardiac conduction abnormalities. Knowledge of the mechanisms of drug interactions has also identified useful interactions with therapeutic benefits, such as in the development of feasible dosing regimens for protease inhibitors in the treatment of HIV and hepatitis C infection. This chapter describes the mechanisms of drug interactions for each of the aforementioned pharmacokinetic processes. The cytochrome P450 family of enzymes, the P-glycoprotein drug transporter, and their mechanisms for inhibition, induction, and suppression are reviewed. Preclinical and clinical methods used to study cytochrome P450 are discussed.


Pharmacokinetics Pharmacodynamics HIV Hepatitis C CYP450 UGT P-glycoprotein OATP Gastric pH Ritonavir Cobicistat Pharmacogenetics Induction Inhibition Tubular secretion Phenotyping 



We would like to thank Kevin C. Brown and Angela D. M. Kashuba for providing us with the text files of this chapter in the previous edition.


  1. 1.
    Guengerich FP, Waterman MR, Egli M (2016) Recent structural insights into cytochrome P450 function. Trends Pharmacol Sci 37(8):625–640PubMedGoogle Scholar
  2. 2.
    Ong CE, Pan Y, Mak JW, Ismail R (2013) In vitro approaches to investigate cytochrome P450 activities: update on current status and their applicability. Expert Opin Drug Metab Toxicol 9(9):1097–1113PubMedGoogle Scholar
  3. 3.
    Rendic S, Guengerich FP (2015) Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol 28(1):38–42PubMedGoogle Scholar
  4. 4.
    Ogawa R, Echizen H (2011) Clinically significant drug interactions with antacids: an update. Drugs 71(14):1839–1864PubMedPubMedCentralGoogle Scholar
  5. 5.
    Ogawa R, Echizen H (2010) Drug-drug interaction profiles of proton pump inhibitors. Clin Pharmacokinet 49(8):509–533PubMedGoogle Scholar
  6. 6.
    Zhang L, Wu F, Lee SC, Zhao H, Zhang L (2014) pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development. Clin Pharmacol Ther 96(2):266–277PubMedGoogle Scholar
  7. 7.
    Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM et al (2016) Effectiveness of Ledipasvir-Sofosbuvir combination in patients with hepatitis C virus infection and factors associated of sustained virologic response. Gastroenterology 151:1131PubMedPubMedCentralGoogle Scholar
  8. 8.
    Falcon RW, Kakuda TN (2008) Drug interactions between HIV protease inhibitors and acid-reducing agents. Clin Pharmacokinet 47(2):75–89PubMedGoogle Scholar
  9. 9.
    Crauwels H, van Heeswijk RP, Stevens M, Buelens A, Vanveggel S, Boven K et al (2013) Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine. AIDS Rev 15(2):87–101PubMedGoogle Scholar
  10. 10.
    Burger DM, Hugen PW, Kroon FP, Groeneveld P, Brinkman K, Foudraine NA et al (1998) Pharmacokinetic interaction between the proton pump inhibitor omeprazole and the HIV protease inhibitor indinavir. AIDS (London, England) 12(15):2080–2082Google Scholar
  11. 11.
    Chin TW, Loeb M, Fong IW (1995) Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole. Antimicrob Agents Chemother 39(8):1671–1675PubMedPubMedCentralGoogle Scholar
  12. 12.
    Kanda Y, Kami M, Matsuyama T, Mitani K, Chiba S, Yazaki Y et al (1998) Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole. Hematol Oncol 16(1):33–37PubMedGoogle Scholar
  13. 13.
    Jaruratanasirikul S, Sriwiriyajan S (1998) Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 54(2):159–161PubMedGoogle Scholar
  14. 14.
    Jaruratanasirikul S, Kleepkaew A (1997) Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole. Eur J Clin Pharmacol 52(3):235–237PubMedGoogle Scholar
  15. 15.
    Moreno F, Hardin TC, Rinaldi MG, Graybill JR (1993) Itraconazole-didanosine excipient interaction. JAMA 269(12):1508PubMedGoogle Scholar
  16. 16.
    Alffenaar JW, van Assen S, van der Werf TS, Kosterink JG, Uges DR (2009) Omeprazole significantly reduces posaconazole serum trough level. Clin Infect Dis Off Publ Infect Dis Soc Am 48(6):839Google Scholar
  17. 17.
    Krishna G, Moton A, Ma L, Medlock MM, McLeod J (2009) Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 53(3):958–966PubMedGoogle Scholar
  18. 18.
    Horowitz HW, Jorde UP, Wormser GP (1992) Drug interactions in use of dapsone for pneumocystis carinii prophylaxis. Lancet (London, England) 339(8795):747Google Scholar
  19. 19.
    Metroka CE, McMechan MF, Andrada R, Laubenstein LJ, Jacobus DP (1991) Failure of prophylaxis with dapsone in patients taking dideoxyinosine. N Engl J Med 325(10):737PubMedGoogle Scholar
  20. 20.
    Kraft WK, Chang PS, van Iersel ML, Waskin H, Krishna G, Kersemaekers WM (2014) Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrob Agents Chemother 58(7):4020–4025PubMedPubMedCentralGoogle Scholar
  21. 21.
    Johnson MD, Hamilton CD, Drew RH, Sanders LL, Pennick GJ, Perfect JR (2003) A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution. J Antimicrob Chemother 51(2):453–457PubMedPubMedCentralGoogle Scholar
  22. 22.
    Knupp CA, Barbhaiya RH (1997) A multiple-dose pharmacokinetic interaction study between didanosine (Videx) and ciprofloxacin (Cipro) in male subjects seropositive for HIV but asymptomatic. Biopharm Drug Dispos 18(1):65–77PubMedGoogle Scholar
  23. 23.
    Polk RE (1989) Drug-drug interactions with ciprofloxacin and other fluoroquinolones. Am J Med 87(5A):76S–81SPubMedGoogle Scholar
  24. 24.
    Sahai J, Gallicano K, Oliveras L, Khaliq S, Hawley-Foss N, Garber G (1993) Cations in the didanosine tablet reduce ciprofloxacin bioavailability. Clin Pharmacol Ther 53(3):292–297PubMedGoogle Scholar
  25. 25.
    Campbell NR, Hasinoff BB (1991) Iron supplements: a common cause of drug interactions. Br J Clin Pharmacol 31(3):251–255PubMedPubMedCentralGoogle Scholar
  26. 26.
    Moss DM, Siccardi M, Murphy M, Piperakis MM, Khoo SH, Back DJ et al (2012) Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob Agents Chemother 56(6):3020–3026PubMedPubMedCentralGoogle Scholar
  27. 27.
    Ramanathan S, Mathias A, Wei X, Shen G, Koziara J, Cheng A et al (2013) Pharmacokinetics of once-daily boosted elvitegravir when administered in combination with acid-reducing agents. J Acquir Immune Defic Syndr 64(1):45–50PubMedGoogle Scholar
  28. 28.
    Song I, Borland J, Arya N, Wynne B, Piscitelli S (2015) Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol 55(5):490–496PubMedGoogle Scholar
  29. 29.
    Yuk JH, Nightingale CH, Quintiliani R, Yeston NS, Orlando R 3rd, Dobkin ED et al (1990) Absorption of ciprofloxacin administered through a nasogastric or a nasoduodenal tube in volunteers and patients receiving enteral nutrition. Diagn Microbiol Infect Dis 13(2):99–102PubMedGoogle Scholar
  30. 30.
    Yuk JH, Nightingale CH, Sweeney KR, Quintiliani R, Lettieri JT, Frost RW (1989) Relative bioavailability in healthy volunteers of ciprofloxacin administered through a nasogastric tube with and without enteral feeding. Antimicrob Agents Chemother 33(7):1118–1120PubMedPubMedCentralGoogle Scholar
  31. 31.
    Greiff JM1, Rowbotham D (1994) Pharmacokinetic drug interactions with gastrointestinal motility modifying agents. 27(6):447—61Google Scholar
  32. 32.
    van Waterschoot RA, Schinkel AH (2011) A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. Pharmacol Rev 63(2):390–410PubMedPubMedCentralGoogle Scholar
  33. 33.
    Knight B, Troutman M, Thakker DR (2006) Deconvoluting the effects of P-glycoprotein on intestinal CYP3A: a major challenge. Curr Opin Pharmacol 6(5):528–532PubMedGoogle Scholar
  34. 34.
    Bertz RJ, Granneman GR (1997) Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 32(3):210–258PubMedGoogle Scholar
  35. 35.
    Peters SA et al. (2016) Predicting drug extraction in the Human Gut Wall: Assessing contributions from drug metabolizing enzymes and transporter proteins using preclinical models. Clin Pharmacokinet 55:673–696Google Scholar
  36. 36.
    Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389–430PubMedGoogle Scholar
  37. 37.
    Komura H, Iwaki M (2011) In vitro and in vivo small intestinal metabolism of CYP3A and UGT substrates in preclinical animals species and humans: species differences. Drug Metab Rev 43(4):476–498PubMedGoogle Scholar
  38. 38.
    Thelen K, Dressman JB (2009) Cytochrome P450-mediated metabolism in the human gut wall. J Pharm Pharmacol 61(5):541–558PubMedGoogle Scholar
  39. 39.
    Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138(1):103–141PubMedPubMedCentralGoogle Scholar
  40. 40.
    Thummel KE, O'Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD et al (1996) Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 59(5):491–502PubMedGoogle Scholar
  41. 41.
    Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ (2011) The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol 7(3):267–286PubMedPubMedCentralGoogle Scholar
  42. 42.
    Seden K, Dickinson L, Khoo S, Back D (2010) Grapefruit-drug interactions. Drugs 70(18):2373–2407PubMedGoogle Scholar
  43. 43.
    Kupferschmidt HH, Fattinger KE, Ha HR, Follath F, Krahenbuhl S (1998) Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br J Clin Pharmacol 45(4):355–359PubMedPubMedCentralGoogle Scholar
  44. 44.
    Kawakami M, Suzuki K, Ishizuka T, Hidaka T, Matsuki Y, Nakamura H (1998) Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects. Int J Clin Pharmacol Ther 36(6):306–308PubMedGoogle Scholar
  45. 45.
    Cheng KL, Nafziger AN, Peloquin CA, Amsden GW (1998) Effect of grapefruit juice on clarithromycin pharmacokinetics. Antimicrob Agents Chemother 42(4):927–929PubMedPubMedCentralGoogle Scholar
  46. 46.
    Kempf DJ, Marsh KC, Kumar G, Rodrigues AD, Denissen JF, McDonald E et al (1997) Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother 41(3):654–660PubMedPubMedCentralGoogle Scholar
  47. 47.
    Hsu A, Granneman GR, Bertz RJ (1998) Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 35(4):275–291PubMedGoogle Scholar
  48. 48.
    Hill A, van der Lugt J, Sawyer W, Boffito M (2009) How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials. AIDS (London, England) 23(17):2237–2245Google Scholar
  49. 49.
    Menon RM, Klein CE, Podsadecki TJ, Chiu YL, Dutta S, Awni WM (2016) Pharmacokinetics and tolerability of paritaprevir, a direct acting antiviral agent for hepatitis C virus treatment, with and without ritonavir in healthy volunteers. Br J Clin Pharmacol 81(5):929–940PubMedPubMedCentralGoogle Scholar
  50. 50.
    Brayer SW, Reddy KR (2015) Ritonavir-boosted protease inhibitor based therapy: a new strategy in chronic hepatitis C therapy. Expert Rev Gastroenterol Hepatol 9(5):547–558PubMedGoogle Scholar
  51. 51.
    Shah BM, Schafer JJ, Priano J, Squires KE (2013) Cobicistat: a new boost for the treatment of human immunodeficiency virus infection. Pharmacotherapy 33(10):1107–1116PubMedGoogle Scholar
  52. 52.
    Nathan B, Bayley J, Waters L, Post FA (2013) Cobicistat: a novel pharmacoenhancer for co-formulation with HIV protease and integrase inhibitors. Infectious diseases and therapy 2(2):111–122PubMedPubMedCentralGoogle Scholar
  53. 53.
    Silva R, Vilas-Boas V, Carmo H, Dinis-Oliveira RJ, Carvalho F, de Lourdes BM et al (2015) Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy. Pharmacol Ther 149:1–123PubMedGoogle Scholar
  54. 54.
    Konig J, Muller F, Fromm MF (2013) Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev 65(3):944–966PubMedGoogle Scholar
  55. 55.
    Estudante M, Morais JG, Soveral G, Benet LZ (2013) Intestinal drug transporters: an overview. Adv Drug Deliv Rev 65(10):1340–1356PubMedGoogle Scholar
  56. 56.
    Mulgaonkar A, Venitz J, Sweet DH (2012) Fluoroquinolone disposition: identification of the contribution of renal secretory and reabsorptive drug transporters. Expert Opin Drug Metab Toxicol 8(5):553–569PubMedGoogle Scholar
  57. 57.
    Pal D, Kwatra D, Minocha M, Paturi DK, Budda B, Mitra AK (2011) Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals. Life Sci 88(21–22):959–971PubMedGoogle Scholar
  58. 58.
    Sevrioukova IF, Poulos TL (2013) Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems. Dalton Trans (Cambridge, England : 2003) 42(9):3116–3126Google Scholar
  59. 59.
    Feng B, Varma MV, Costales C, Zhang H, Tremaine L (2014) In vitro and in vivo approaches to characterize transporter-mediated disposition in drug discovery. Expert Opin Drug Discovery 9(8):873–890Google Scholar
  60. 60.
    Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215–236PubMedGoogle Scholar
  61. 61.
    Salama NN, Eddington ND, Fasano A (2006) Tight junction modulation and its relationship to drug delivery. Adv Drug Deliv Rev 58(1):15–28PubMedGoogle Scholar
  62. 62.
    Assimakopoulos SF, Dimitropoulou D, Marangos M, Gogos CA (2014) Intestinal barrier dysfunction in HIV infection: pathophysiology, clinical implications and potential therapies. Infection 42(6):951–959PubMedGoogle Scholar
  63. 63.
    Zakeri-Milani P, Valizadeh H (2014) Intestinal transporters: enhanced absorption through P-glycoprotein-related drug interactions. Expert Opin Drug Metab Toxicol 10(6):859–871PubMedGoogle Scholar
  64. 64.
    Glaeser H (2011) Importance of P-glycoprotein for drug-drug interactions. Handb Exp Pharmacol 201:285–297Google Scholar
  65. 65.
    Lown KS, Fontana RJ, Schmiedlin-Ren P et al (1995) Interindividual variation in intestinal mdr1:lack of short diet effects. Gastroenterology 108:A737Google Scholar
  66. 66.
    Lamba J, Strom S, Venkataramanan R, Thummel KE, Lin YS, Liu W et al (2006) MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype. Clin Pharmacol Ther 79(4):325–338PubMedGoogle Scholar
  67. 67.
    Wakasugi H, Yano I, Ito T, Hashida T, Futami T, Nohara R et al (1998) Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther 64(1):123–128PubMedPubMedCentralGoogle Scholar
  68. 68.
    Cormet-Boyaka E, Huneau JF, Mordrelle A, Boyaka PN, Carbon C, Rubinstein E et al (1998) Secretion of sparfloxacin from the human intestinal Caco-2 cell line is altered by P-glycoprotein inhibitors. Antimicrob Agents Chemother 42(10):2607–2611PubMedPubMedCentralGoogle Scholar
  69. 69.
    Srinivas RV, Middlemas D, Flynn P, Fridland A (1998) Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother 42(12):3157–3162PubMedPubMedCentralGoogle Scholar
  70. 70.
    Neumanova Z, Cerveny L, Ceckova M, Staud F (2014) Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta. AIDS (London, England) 28(1):9–17Google Scholar
  71. 71.
    Lempers VJ, van den Heuvel JJ, Russel FG, Aarnoutse RE, Burger DM, Bruggemann RJ et al (2016) Inhibitory potential of antifungal drugs on ATP-binding cassette transporters P-glycoprotein, MRP1 to MRP5, BCRP, and BSEP. Antimicrob Agents Chemother 60(6):3372–3379PubMedPubMedCentralGoogle Scholar
  72. 72.
    Kirby BJ, Symonds WT, Kearney BP, Mathias AA (2015) Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor Sofosbuvir. Clin Pharmacokinet 54(7):677–690Google Scholar
  73. 73.
    Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T (1998) Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol 358(3):289–294PubMedGoogle Scholar
  74. 74.
    Sansom LN, Evans AM (1995) What is the true clinical significance of plasma protein binding displacement interactions? Drug Saf 12(4):227–233PubMedGoogle Scholar
  75. 75.
    Onufrak NJ, Forrest A, Gonzalez D (2016) Pharmacokinetic and pharmacodynamic principles of anti-infective dosing. Clin Ther 38:1930PubMedPubMedCentralGoogle Scholar
  76. 76.
    Barbour A, Scaglione F, Derendorf H (2010) Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices. Int J Antimicrob Agents 35(5):431–438PubMedGoogle Scholar
  77. 77.
    Boffito M, Back DJ, Blaschke TF, Rowland M, Bertz RJ, Gerber JG et al (2003) Protein binding in antiretroviral therapies. AIDS Res Hum Retrovir 19(9):825–835Google Scholar
  78. 78.
    Back DJ, Burger DM (2015) Interaction between amiodarone and sofosbuvir-based treatment for hepatitis C virus infection: potential mechanisms and lessons to be learned. Gastroenterology 149(6):1315–1317PubMedGoogle Scholar
  79. 79.
    Rolan PE (1994) Plasma protein binding displacement interactions--why are they still regarded as clinically important? Br J Clin Pharmacol 37(2):125–128PubMedPubMedCentralGoogle Scholar
  80. 80.
    Schmidt S, Gonzalez D, Derendorf H (2010) Significance of protein binding in pharmacokinetics and pharmacodynamics. J Pharm Sci 99(3):1107–1122PubMedGoogle Scholar
  81. 81.
    Benet LZ, Hoener BA (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71(3):115–121PubMedGoogle Scholar
  82. 82.
    Schmidt S, Barbour A, Sahre M, Rand KH, Derendorf H (2008) PK/PD: new insights for antibacterial and antiviral applications. Curr Opin Pharmacol 8(5):549–556PubMedGoogle Scholar
  83. 83.
    Nelson DR (2006) Cytochrome P450 nomenclature, 2004. Methods Mol Biol 320:1–10PubMedGoogle Scholar
  84. 84.
    Martiny VY, Miteva MA (2013) Advances in molecular modeling of human cytochrome P450 polymorphism. J Mol Biol 425(21):3978–3992PubMedGoogle Scholar
  85. 85.
    Murray M (1997) Drug-mediated inactivation of cytochrome P450. Clin Exp Pharmacol Physiol 24(7):465–470PubMedGoogle Scholar
  86. 86.
    Vanden Bossche H, Koymans L, Moereels H (1995) P450 inhibitors of use in medical treatment: focus on mechanisms of action. Pharmacol Ther 67(1):79–100Google Scholar
  87. 87.
    Ma Q, Lu AY (2011) Pharmacogenetics pharmacogenomics, and individualized medicine. Pharmacol Rev 63(2):437–459PubMedGoogle Scholar
  88. 88.
    Michaud V, Bar-Magen T, Turgeon J, Flockhart D, Desta Z, Wainberg MA (2012) The dual role of pharmacogenetics in HIV treatment: mutations and polymorphisms regulating antiretroviral drug resistance and disposition. Pharmacol Rev 64(3):803–833PubMedGoogle Scholar
  89. 89.
    Backman JT, Filppula AM, Niemi M, Neuvonen PJ (2016) Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev 68(1):168–241PubMedGoogle Scholar
  90. 90.
    Werk AN, Cascorbi I (2014) Functional gene variants of CYP3A4. Clin Pharmacol Ther 96(3):340–348PubMedGoogle Scholar
  91. 91.
    Naidoo P, Chetty VV, Chetty M (2014) Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz. Eur J Clin Pharmacol 70(4):379–389PubMedGoogle Scholar
  92. 92.
    Semvua HH, Mtabho CM, Fillekes Q, van den Boogaard J, Kisonga RM, Mleoh L et al (2013) Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Antivir Ther 18(1):105–113PubMedGoogle Scholar
  93. 93.
    van Luin M, Brouwer AM, van der Ven A, de Lange W, van Schaik RH, Burger DM (2009) Efavirenz dose reduction to 200 mg once daily in a patient treated with rifampicin. AIDS (London, England) 23(6):742–744Google Scholar
  94. 94.
    Zhu L, Bruggemann RJ, Uy J, Colbers A, Hruska MW, Chung E et al (2016) CYP2C19 genotype-dependent pharmacokinetic drug interaction between voriconazole and ritonavir-boosted atazanavir in healthy subjects. J Clin PharmacolGoogle Scholar
  95. 95.
    Kamel A, Harriman S (2013) Inhibition of cytochrome P450 enzymes and biochemical aspects of mechanism-based inactivation (MBI). Drug Discov Today Technol 10(1):e177–e189PubMedGoogle Scholar
  96. 96.
    Greenblatt DJ (2014) In vitro prediction of clinical drug interactions with CYP3A substrates: we are not there yet. Clin Pharmacol Ther 95(2):133–135PubMedGoogle Scholar
  97. 97.
    Brown HS, Galetin A, Hallifax D, Houston JB (2006) Prediction of in vivo drug-drug interactions from in vitro data : factors affecting prototypic drug-drug interactions involving CYP2C9, CYP2D6 and CYP3A4. Clin Pharmacokinet 45(10):1035–1050PubMedGoogle Scholar
  98. 98.
    Hisaka A, Ohno Y, Yamamoto T, Suzuki H (2010) Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. Pharmacol Ther 125(2):230–248PubMedGoogle Scholar
  99. 99.
    Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H (2008) Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol 82(10):667–715PubMedGoogle Scholar
  100. 100.
    Ke AB, Zamek-Gliszczynski MJ, Higgins JW, Hall SD (2014) Itraconazole and clarithromycin as ketoconazole alternatives for clinical CYP3A inhibition studies. Clin Pharmacol Ther 95(5):473–476PubMedGoogle Scholar
  101. 101.
    Zhou S, Yung Chan S, Cher Goh B, Chan E, Duan W, Huang M et al (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet 44(3):279–304PubMedGoogle Scholar
  102. 102.
    Trenholme GM, Williams RL, Rieckmann KH, Frischer H, Carson PE (1976) Quinine disposition during malaria and during induced fever. Clin Pharmacol Ther 19(4):459–467PubMedPubMedCentralGoogle Scholar
  103. 103.
    Lee JI, Zhang L, Men AY, Kenna LA, Huang SM (2010) CYP-mediated therapeutic protein-drug interactions: clinical findings, proposed mechanisms and regulatory implications. Clin Pharmacokinet 49(5):295–310PubMedGoogle Scholar
  104. 104.
    Morgan ET (2009) Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther 85(4):434–438PubMedPubMedCentralGoogle Scholar
  105. 105.
    Aitken AE, Richardson TA, Morgan ET (2006) Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol 46:123–149Google Scholar
  106. 106.
    Zhu M, Kaul S, Nandy P, Grasela DM, Pfister M (2009) Model-based approach to characterize efavirenz autoinduction and concurrent enzyme induction with carbamazepine. Antimicrob Agents Chemother 53(6):2346–2353PubMedPubMedCentralGoogle Scholar
  107. 107.
    Smythe W, Khandelwal A, Merle C, Rustomjee R, Gninafon M, Bocar Lo M et al (2012) A semimechanistic pharmacokinetic-enzyme turnover model for rifampin autoinduction in adult tuberculosis patients. Antimicrob Agents Chemother 56(4):2091–2098PubMedPubMedCentralGoogle Scholar
  108. 108.
    Rana R, Chen Y, Ferguson SS, Kissling GE, Surapureddi S, Goldstein JA (2010) Hepatocyte nuclear factor 4{alpha} regulates rifampicin-mediated induction of CYP2C genes in primary cultures of human hepatocytes. Drug Metab Dispos 38(4):591–599PubMedPubMedCentralGoogle Scholar
  109. 109.
    Fahmi OA, Ripp SL (2010) Evaluation of models for predicting drug-drug interactions due to induction. Expert Opin Drug Metab Toxicol 6(11):1399–1416PubMedGoogle Scholar
  110. 110.
    Sinz M, Wallace G, Sahi J (2008) Current industrial practices in assessing CYP450 enzyme induction: preclinical and clinical. AAPS J 10(2):391–400PubMedPubMedCentralGoogle Scholar
  111. 111.
    Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski CJ, LeCluyse EL et al (2007) Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 320(1):72–80PubMedGoogle Scholar
  112. 112.
    Zangar RC, Bollinger N, Verma S, Karin NJ, Lu Y (2008) The nuclear factor-kappa B pathway regulates cytochrome P450 3A4 protein stability. Mol Pharmacol 73(6):1652–1658PubMedGoogle Scholar
  113. 113.
    Wu B, Kulkarni K, Basu S, Zhang S, Hu M (2011) First-pass metabolism via UDP-glucuronosyltransferase: a barrier to oral bioavailability of phenolics. J Pharm Sci 100(9):3655–3681PubMedPubMedCentralGoogle Scholar
  114. 114.
    Devineni D, Vaccaro N, Murphy J, Curtin C, Mamidi RN, Weiner S et al (2015) Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants. Int J Clin Pharmacol Ther 53(2):115–128PubMedGoogle Scholar
  115. 115.
    Walsky RL, Bauman JN, Bourcier K, Giddens G, Lapham K, Negahban A et al (2012) Optimized assays for human UDP-glucuronosyltransferase (UGT) activities: altered alamethicin concentration and utility to screen for UGT inhibitors. Drug Metab Dispos 40(5):1051–1065PubMedGoogle Scholar
  116. 116.
    Belanger AS, Caron P, Harvey M, Zimmerman PA, Mehlotra RK, Guillemette C (2009) Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab Dispos 37(9):1793–1796PubMedPubMedCentralGoogle Scholar
  117. 117.
    Burger DM, Huisman A, Van Ewijk N, Neisingh H, Van Uden P, Rongen GA et al (2008) The effect of atazanavir and atazanavir/ritonavir on UDP-glucuronosyltransferase using lamotrigine as a phenotypic probe. Clin Pharmacol Ther 84(6):698–703PubMedGoogle Scholar
  118. 118.
    van der Lee MJ, Dawood L, ter Hofstede HJ, de Graaff-Teulen MJ, van Ewijk-Beneken Kolmer EW, Caliskan-Yassen N et al (2006) Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects. Clin Pharmacol Ther 80(2):159–168PubMedGoogle Scholar
  119. 119.
    Sim SC, Kacevska M, Ingelman-Sundberg M (2013) Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J 13(1):1–11PubMedGoogle Scholar
  120. 120.
    Yiannakopoulou E (2013) Pharmacogenomics of phase II metabolizing enzymes and drug transporters: clinical implications. Pharmacogenomics J 13(2):105–109PubMedGoogle Scholar
  121. 121.
    Perwitasari DA, Atthobari J, Wilffert B (2015) Pharmacogenetics of isoniazid-induced hepatotoxicity. Drug Metab Rev 47(2):222–228PubMedGoogle Scholar
  122. 122.
    Knights KM, Rowland A, Miners JO (2013) Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol 76(4):587–602PubMedPubMedCentralGoogle Scholar
  123. 123.
    Jansen A, Colbers EP, van der Ven AJ, Richter C, Rockstroh JK, Wasmuth JC et al (2013) Pharmacokinetics of the combination raltegravir/atazanavir in HIV-1-infected patients. HIV Med 14(7):449–452PubMedGoogle Scholar
  124. 124.
    Bollen P, Reiss P, Schapiro J, Burger D (2015) Clinical pharmacokinetics and pharmacodynamics of dolutegravir used as a single tablet regimen for the treatment of HIV-1 infection. Expert Opin Drug Saf 14(9):1457–1472PubMedGoogle Scholar
  125. 125.
    Regazzi M, Carvalho AC, Villani P, Matteelli A (2014) Treatment optimization in patients co-infected with HIV and mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins. Clin Pharmacokinet 53(6):489–507PubMedGoogle Scholar
  126. 126.
    Higgins LG, Hayes JD (2011) Mechanisms of induction of cytosolic and microsomal glutathione transferase (GST) genes by xenobiotics and pro-inflammatory agents. Drug Metab Rev 43(2):92–137PubMedGoogle Scholar
  127. 127.
    Nijland HM, Ruslami R, Suroto AJ, Burger DM, Alisjahbana B, van Crevel R et al (2007) Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis. Clin Infect Dis Off Publ Infect Dis Soc Am 45(8):1001–1007Google Scholar
  128. 128.
    Weiner M, Burman W, Luo CC, Peloquin CA, Engle M, Goldberg S et al (2007) Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin. Antimicrob Agents Chemother 51(8):2861–2866PubMedPubMedCentralGoogle Scholar
  129. 129.
    Feng B, LaPerle JL, Chang G, Varma MV (2010) Renal clearance in drug discovery and development: molecular descriptors, drug transporters and disease state. Expert Opin Drug Metab Toxicol 6(8):939–952PubMedGoogle Scholar
  130. 130.
    Yombi JC, Pozniak A, Boffito M, Jones R, Khoo S, Levy J et al (2014) Antiretrovirals and the kidney in current clinical practice: renal pharmacokinetics, alterations of renal function and renal toxicity. AIDS (London, England) 28(5):621–632Google Scholar
  131. 131.
    Morrissey KM, Stocker SL, Wittwer MB, Xu L, Giacomini KM (2013) Renal transporters in drug development. Annu Rev Pharmacol Toxicol 53:503–529PubMedGoogle Scholar
  132. 132.
    Kampmann J, Hansen JM, Siersboek-Nielsen K, Laursen H (1972) Effect of some drugs on penicillin half-life in blood. Clin Pharmacol Ther 13(4):516–519PubMedGoogle Scholar
  133. 133.
    Douros A, Grabowski K, Stahlmann R (2015) Safety issues and drug-drug interactions with commonly used quinolones. Expert Opin Drug Metab Toxicol 11(1):25–39PubMedGoogle Scholar
  134. 134.
    Cohen O, Locketz G, Hershko AY, Gorshtein A, Levy Y (2015) Colchicine-clarithromycin-induced rhabdomyolysis in familial mediterranean fever patients under treatment for helicobacter pylori. Rheumatol Int 35(11):1937–1941PubMedGoogle Scholar
  135. 135.
    Bruggemann RJ, Alffenaar JW, Blijlevens NM, Billaud EM, Kosterink JG, Verweij PE et al (2009) Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis Off Publ Infect Dis Soc Am 48(10):1441–1458Google Scholar
  136. 136.
    Woytowish MR, Maynor LM (2013) Clinical relevance of linezolid-associated serotonin toxicity. Ann Pharmacother 47(3):388–397PubMedGoogle Scholar
  137. 137.
    Owens RC Jr, Nolin TD (2006) Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis Off Publ Infect Dis Soc Am 43(12):1603–1611Google Scholar
  138. 138.
    Chen J, Raymond K (2006) Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob 5:3PubMedPubMedCentralGoogle Scholar
  139. 139.
    Semvua HH, Kibiki GS, Kisanga ER, Boeree MJ, Burger DM, Aarnoutse R (2015) Pharmacological interactions between rifampicin and antiretroviral drugs: challenges and research priorities for resource-limited settings. Ther Drug Monit 37(1):22–32PubMedGoogle Scholar
  140. 140.
    Langness JA, Everson GT (2016) Viral hepatitis: drug-drug interactions in HCV treatment--the good, the bad and the ugly. Nat Rev Gastroenterol Hepatol 13(4):194–195PubMedGoogle Scholar
  141. 141.
    Burger D, Back D, Buggisch P, Buti M, Craxi A, Foster G et al (2013) Clinical management of drug-drug interactions in HCV therapy: challenges and solutions. J Hepatol 58(4):792–800PubMedGoogle Scholar
  142. 142.
    Larson KB, Wang K, Delille C, Otofokun I, Acosta EP (2014) Pharmacokinetic enhancers in HIV therapeutics. Clin Pharmacokinet 53(10):865–872PubMedGoogle Scholar
  143. 143.
    FDA. Guidance for Industry. Drug interaction studies — study design, data analysis, implications for dosing, and labeling recommendations 2012 [September 13, 2016]. Available from:
  144. 144.
    Stringer RA, Strain-Damerell C, Nicklin P, Houston JB (2009) Evaluation of recombinant cytochrome P450 enzymes as an in vitro system for metabolic clearance predictions. Drug Metab Dispos Biol Fate Chem 37(5):1025–1034PubMedGoogle Scholar
  145. 145.
    Spaggiari D, Geiser L, Daali Y, Rudaz S (2014) A cocktail approach for assessing the in vitro activity of human cytochrome P450s: an overview of current methodologies. J Pharm Biomed Anal 101:221–237PubMedGoogle Scholar
  146. 146.
    Khojasteh SC, Prabhu S, Kenny JR, Halladay JS, Lu AY (2011) Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur J Drug Metab Pharmacokinet 36(1):1–16PubMedGoogle Scholar
  147. 147.
    Parkinson A, Kazmi F, Buckley DB, Yerino P, Ogilvie BW, Paris BL (2010) System-dependent outcomes during the evaluation of drug candidates as inhibitors of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes: human hepatocytes versus liver microsomes versus recombinant enzymes. Drug Metab Pharmacokinet 25(1):16–27PubMedGoogle Scholar
  148. 148.
    Donato MT, Lahoz A, Castell JV, Gomez-Lechon MJ (2008) Cell lines: a tool for in vitro drug metabolism studies. Curr Drug Metab 9(1):1–11PubMedGoogle Scholar
  149. 149.
    Alqahtani S, Mohamed LA, Kaddoumi A (2013) Experimental models for predicting drug absorption and metabolism. Expert Opin Drug Metab Toxicol 9(10):1241–1254PubMedGoogle Scholar
  150. 150.
    Scotcher D, Jones C, Posada M, Rostami-Hodjegan A, Galetin A (2016) Key to opening kidney for in vitro-in vivo extrapolation entrance in health and disease: part I: in vitro systems and physiological data. AAPS JPubMedGoogle Scholar
  151. 151.
    Graaf IA, Groothuis GM, Olinga P (2007) Precision-cut tissue slices as a tool to predict metabolism of novel drugs. Expert Opin Drug Metab Toxicol 3(6):879–898PubMedGoogle Scholar
  152. 152.
    de Graaf IA, Olinga P, de Jager MH, Merema MT, de Kanter R, van de Kerkhof EG et al (2010) Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat Protoc 5(9):1540–1551PubMedGoogle Scholar
  153. 153.
    Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S et al (2013) Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 87(8):1315–1530PubMedPubMedCentralGoogle Scholar
  154. 154.
    Olinga P, Schuppan D (2013) Precision-cut liver slices: a tool to model the liver ex vivo. J Hepatol 58(6):1252–1253PubMedGoogle Scholar
  155. 155.
    Lash LH, Putt DA, Cai H (2008) Drug metabolism enzyme expression and activity in primary cultures of human proximal tubular cells. Toxicology 244(1):56–65PubMedGoogle Scholar
  156. 156.
    Peters SA, Jones CR, Ungell AL, Hatley OJ (2016) Predicting drug extraction in the human gut wall: assessing contributions from drug metabolizing enzymes and transporter proteins using preclinical models. Clin Pharmacokinet 55(6):673–696PubMedPubMedCentralGoogle Scholar
  157. 157.
    Moss DM, Marzolini C, Rajoli RK, Siccardi M (2015) Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies. Expert Opin Drug Metab Toxicol 11(8):1203–1217PubMedPubMedCentralGoogle Scholar
  158. 158.
    Rostami-Hodjegan A (2012) Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther 92(1):50–61PubMedGoogle Scholar
  159. 159.
    Chu X, Bleasby K, Evers R (2013) Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol 9(3):237–252PubMedGoogle Scholar
  160. 160.
    Graham MJ, Lake BG (2008) Induction of drug metabolism: species differences and toxicological relevance. Toxicology 254(3):184–191PubMedGoogle Scholar
  161. 161.
    Martignoni M, Groothuis GM, de Kanter R (2006) Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2(6):875–894PubMedGoogle Scholar
  162. 162.
    Fuhr U, Jetter A, Kirchheiner J (2007) Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther 81(2):270–283PubMedGoogle Scholar
  163. 163.
    De Kesel PM, Lambert WE, Stove CP (2016) Alternative sampling strategies for cytochrome P450 phenotyping. Clin Pharmacokinet 55(2):169–184PubMedGoogle Scholar
  164. 164.
    Breimer DD, Schellens JH (1990) A ‘cocktail’ strategy to assess in vivo oxidative drug metabolism in humans. Trends Pharmacol Sci 11(6):223–225PubMedGoogle Scholar
  165. 165.
    Pretorius E, Klinker H, Rosenkranz B (2011) The role of therapeutic drug monitoring in the management of patients with human immunodeficiency virus infection. Ther Drug Monit 33(3):265–274PubMedGoogle Scholar
  166. 166.
    Alsultan A, Peloquin CA (2014) Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs 74(8):839–854PubMedGoogle Scholar
  167. 167.
    Bruggemann RJ, Aarnoutse RE (2015) Fundament and prerequisites for the application of an antifungal TDM service. Curr Fungal Infect Rep 9(2):122–129PubMedPubMedCentralGoogle Scholar
  168. 168.
    Croes S, Koop AH, van Gils SA, Neef C (2012) Efficacy, nephrotoxicity and ototoxicity of aminoglycosides, mathematically modelled for modelling-supported therapeutic drug monitoring. Eur J Pharm Sci Off J Eur Fed Pharm Sci 45(1–2):90–100Google Scholar
  169. 169.
    Ye ZK, Li C, Zhai SD (2014) Guidelines for therapeutic drug monitoring of vancomycin: a systematic review. PLoS One 9(6):e99044PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • David M. Burger
    • 1
  • Lindsey H. M. te Brake
    • 1
  • Rob E. Aarnoutse
    • 1
  1. 1.Department of PharmacyRadboud University Medical CenterNijmegenThe Netherlands

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