Psychopharmacology

, Volume 173, Issue 1–2, pp 132–138 | Cite as

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

  • Jun-Sheng Wang
  • Ying Ruan
  • Robin M. Taylor
  • Jennifer L. Donovan
  • John S. Markowitz
  • C. Lindsay DeVane
Original Investigation

Abstract

Rationale

Methadone maintenance treatment is complicated by the wide variability of efficacy among patients. The large interindividual variability of the plasma concentrations of methadone was previously thought to be responsible for the variable therapeutic efficacy. However, recent studies suggested that methadone may be a substrate of P-glycoprotein (P-gp). Therefore, the function of P-gp in blood–brain barrier (BBB) may affect the concentration of methadone at its site(s) of action in the central nervous system, thereby contributing to its therapeutic efficacy and/or adverse events.

Objective

To investigate the effect of P-gp on brain penetration of methadone (R)- and (S)-enantiomers and their major oxidative metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP).

Methods

We compared the tissue distribution of methadone (R)- and (S)-enantiomers and EDDP in the Abcb1a−/− gene knockout mice and the Abcb1a+/+ wild-type mice 1 h following intraperitoneal administration of 15 μg Rac-methadone/g mouse.

Results

Plasma concentrations of (R)- and (S)-methadone were similar between the two animal groups. However, the brain concentrations of (R)- and (S)-methadone in the Abcb1a−/− mice were markedly higher (15- and 23-fold, respectively, P<0.0001) than those of the Abcb1a+/+ wild-type mice. No statistically significant difference was found for other organs between the mutants and controls. No organ difference was found for EDDP between the mutants and controls.

Conclusions

(R)- and (S)-methadone are substrates of P-gp. The P-gp in BBB greatly limits the brain entry of (R)- and (S)-methadone to their central nervous system acting sites. The interindividual variation in expression of P-gp in BBB may represent a source of variation for the access and effects of methadone in the brain.

Keywords

Methadone P-glycoprotein Abcb1 Blood–brain barrier 

Notes

Acknowledgements

This work was partly supported by Public Health Service grant DA-13027. None of the authors has conflicting interests that interfere with the integrity of the content of the article.

References

  1. Aquilante CL, Letrent SP, Pollack GM, Brouwer KL (2000) Increased brain P-glycoprotein in morphine tolerant rats. Life Sci 64:47–51Google Scholar
  2. Bell J, Bowron P, Lewis J, Batey R (1990) Serum levels of methadone in maintenance clients who persist in illicit drug use. Br J Addict 85:1599–1602PubMedGoogle Scholar
  3. Bouer R, Barthe L, Philibert C, Tournaire C, Woodley J, Houin G (1999) 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 13:494–500PubMedGoogle Scholar
  4. Boulton DW, DeVane C (2000) Development and application of a chiral high-performance liquid chromatography assay for pharmacokinetic studies of methadone. Chirality 12:681–687CrossRefPubMedGoogle Scholar
  5. Boulton DW, Arnaud P, DeVane CL (2001) Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate. Clin Pharmacol Ther 70:48–57CrossRefPubMedGoogle Scholar
  6. Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB (2000) Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 28:655–660PubMedGoogle Scholar
  7. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A 86:695–698PubMedGoogle Scholar
  8. Eap CB, Bourquin M, Martin J, Spagnoli J, Livoti S, Powell K, Baumann P, Deglon J (2000) Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend 61:47–54CrossRefPubMedGoogle Scholar
  9. Eap CB, Buclin T, Baumann P (2002) Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 41:1153–1193PubMedGoogle Scholar
  10. Farrell M, Ward J, Mattick R, Hall W, Stimson GV, des Jarlais D, Gossop M, Strang J (1994) Methadone maintenance treatment in opiate dependence: a review. BMJ 309:997–1001PubMedGoogle Scholar
  11. Foster DJ, Somogyi AA, Bochner F (1999) Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 47:403–412CrossRefPubMedGoogle Scholar
  12. Fromm MF (2000) P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 38:69–74PubMedGoogle Scholar
  13. Garrido MJ, Troconiz IF (1999) Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 42:61–66CrossRefPubMedGoogle Scholar
  14. Hagen NA, Wasylenko E (1999) Methadone: outpatient titration and monitoring strategies in cancer patients. J Pain Symptom Manage 18:369–375CrossRefPubMedGoogle Scholar
  15. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97:3473–3478PubMedGoogle Scholar
  16. Holash JA, Harik SI, Perry G, Stewart PA (1993) Barrier properties of testis microvessels. Proc Natl Acad Sci U S A 90:11069–11073PubMedGoogle Scholar
  17. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000) A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 343:1290–1297PubMedGoogle Scholar
  18. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR (1998) The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 101:289–294PubMedGoogle Scholar
  19. Kreek MJ, Oratz M, Rothschild MA (1978) Hepatic extraction of long- and short-acting narcotics in the isolated perfused rabbit liver. Gastroenterology 75:88–94PubMedGoogle Scholar
  20. Kristensen K, Christensen CB, Christrup LL (1995) The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 56:PL45–PL50CrossRefPubMedGoogle Scholar
  21. Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, Ohdo S, Ohtani H, Sawada Y, Higuchi S, Otsubo K (2002) Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 72:209–219CrossRefPubMedGoogle Scholar
  22. Letrent SP, Pollack GM, Brouwer KR, Brouwer KL (1999) Effects of a potent and specific P-glycoprotein inhibitor on the blood–brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metab Dispos 27:827–834PubMedGoogle Scholar
  23. Lin JH, Yamazaki M (2003) Role of p-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59–98PubMedGoogle Scholar
  24. Ling W, Wesson DR, Charuvastra C, Klett CJ (1996) A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry 53:401–407PubMedGoogle Scholar
  25. Loimer N, Schmid R, Grunberger J, Jagsch R, Linzmayer L, Presslich O (1991) Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels. Psychopharmacology 103:538–540PubMedGoogle Scholar
  26. Lotsch J, Schmidt R, Vetter G, Schmidt H, Niederberger E, Geisslinger G, Tegeder I (2002) Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein. J Neurochem 83:241–248CrossRefPubMedGoogle Scholar
  27. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW (2002) Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther 303:1029–1037CrossRefPubMedGoogle Scholar
  28. Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T, Matsuo M, Kasuga M, Okumura K (2002) Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 71:297–303CrossRefPubMedGoogle Scholar
  29. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS (2001) Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther 299:620–628PubMedGoogle Scholar
  30. Potschka H, Loscher W (2001) In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood–brain barrier of rats. Epilepsia 42:1231–1240CrossRefPubMedGoogle Scholar
  31. Potschka H, Fedrowitz M, Loscher W (2001) P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 12:3557-3560CrossRefPubMedGoogle Scholar
  32. Potschka H, Fedrowitz M, Loscher W (2002) P-Glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood–brain barrier: evidence from microdialysis experiments in rats. Neurosci Lett 327:173-176CrossRefPubMedGoogle Scholar
  33. Preston KL, Umbricht A, Epstein DH (2000) Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance. Arch Gen Psychiatry 57:395–404PubMedGoogle Scholar
  34. Rhoades HM, Creson D, Elk R, Schmitz J, Grabowski J (1998) Retention, HIV risk, and illicit drug use during treatment: methadone dose and visit frequency. Am J Public Health 88:34–39PubMedGoogle Scholar
  35. Riordan JR, Deuchars K, Kartner N, Alon N, Trent J, Ling V (1985) Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature 316:817–819PubMedGoogle Scholar
  36. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HPJ, Berns AJM, Borst P (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77:491–502PubMedGoogle Scholar
  37. Schinkel AH, Wagenaar E, Mol CA, van Deemter L (1996) P-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517–2524PubMedGoogle Scholar
  38. Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JM, Fibbe WE, Borst P (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A 94:4028–4033PubMedGoogle Scholar
  39. Scott CC, Robbins EB, Chen KK (1948) Pharmacologic comparison of the optical isomers of methadone. J Pharmacol Exp Ther 93:282–286Google Scholar
  40. Shah NS, Donald AG, Bertolatus JA, Hixson B (1976) Tissue distribution of levo-methadone in nonpregnant and female and male mice: effect of SKF 525-A 1,2. J Pharmacol Exp Ther 199:103–116PubMedGoogle Scholar
  41. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 348:1442–1448CrossRefPubMedGoogle Scholar
  42. Silverman JA (2000) P-glycoprotein. In: Levy R (ed) Metabolic drug interactions. Lippincott-Raven, Philadelphia, pp 135–144Google Scholar
  43. Strain EC, Bigelow GE, Liebson IA, Stitzer ML (1999) Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. JAMA 281:1000–1005PubMedGoogle Scholar
  44. Sullivan HR, Due SL (1973) Urinary metabolites of dl-methadone in maintenance subjects. J Med Chem 16:909–913PubMedGoogle Scholar
  45. Thompson SJ, Koszdin K, Bernards CM (2000) Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 92:1392–1399PubMedGoogle Scholar
  46. Uhr M, Grauer MT (2003) abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res 37:179–185CrossRefPubMedGoogle Scholar
  47. Uhr M, Steckler T, Yassouridis A, Holsboer F (2000) Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood–brain barrier deficiency due to mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology 22:380–387CrossRefPubMedGoogle Scholar
  48. Uhr M, Holsboer F, Muller MB (2002) Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b P-glycoproteins. J Neuroendocrinol 14:753–759CrossRefPubMedGoogle Scholar
  49. Umbenhauer DR, Lankas GR, Pippert TR, Wise LD, Cartwright ME, Hall SJ, Beare CM (1997) Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol Appl Pharmacol 146:88–94CrossRefPubMedGoogle Scholar
  50. Wang JS, DeVane CL (2003) Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 31:742–747CrossRefPubMedGoogle Scholar
  51. Wang JS, Taylor R, Runa Y, Donovan LJ, Markowitz SJ, DeVane CL (2004) Olanzapine penetration into brain is greater in transgenic mdr1a p-glycoprotein deficient mice than FVB1 (wild type) animals. Neuropsychopharmacology (in press)Google Scholar
  52. Yu DK (1999) The contribution of P-glycoprotein to pharmacokinetic drug–drug interactions. J Clin Pharmacol 39:1203–1211PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Jun-Sheng Wang
    • 1
  • Ying Ruan
    • 1
  • Robin M. Taylor
    • 1
  • Jennifer L. Donovan
    • 1
  • John S. Markowitz
    • 2
  • C. Lindsay DeVane
    • 1
  1. 1.Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral SciencesMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Pharmaceutical SciencesMedical University of South CarolinaCharlestonUSA

Personalised recommendations