In vitro P-Glycoprotein-Mediated Transport of (R)-, (S)-, (R,S)-Methadone, LAAM and Their Main MetabolitesCrettol S. · Digon P. · Powell Golay K. · Brawand M. · Eap C.B.
Unité de Biochimie et Psychopharmacologie Clinique, Centre de Neurosciences Psychiatriques, Département de Psychiatrie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Hôpital de Cery, Prilly-Lausanne, Suisse
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Methadone and L-α-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P-gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1-transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM.
© 2007 S. Karger AG, Basel
- Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 2002;41:1153–1193.
- Crettol S, Déglon JJ, Besson J, Croquette-Krokkar M, Hämmig R, Gothuey I, Monnat M, Eap CB: ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006;80:668–681.
- Sullivan HR, Due SL: Urinary metabolites of dl-methadone in maintenance subjects. J Med Chem 1973;16:909–913.
- Moody DE, Alburges ME, Parker RJ, Collins JM, Strong JM: The involvement of cytochrome P450 3A4 in the N-demethylation of L-α-acetylmethadol (LAAM), norlaam, and methadone. Drug Metab Dispos 1997;25:1347–1353.
- Neff JA, Moody DE: Differential N-demethylation of L-alpha-acetylmethadol (LAAM) and norLAAM by cytochrome P450s 2B6, 2C18, and 3A4. Biochem Biophys Res Commun 2001;284:751–756.
- Billings RE, Booher R, Smits S, Pohland A, McMahon RE: Metabolism of acetylmethadol. A sensitive assay for noracetylmethadol and the identification of a new active metabolite. J Med Chem 1973;16:305–306.
Horng JS, Smits SE, Wong DT: The binding of the optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives to the opiate receptors of rat brain. Res Commun Chem Pathol Pharmacol 1976;14:621–629.
- Deamer RL, Wilson DR, Clark DS, Prichard JG: Torsades de pointes associated with dose levomethadyl acetate (ORLAAM). J Addict Dis 2001;20:7–14.
Food and Drug Administration, Center for Drug Evaluation and Research: Product Discontinuation Notice for ORLAAM 10.2003. www.fda.gov/cder/drug/shortages/orlaam.htm.
- Juliano RL, Ling V: A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455:152–162.
- Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC: Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987;84:7735–7738.
- Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989;86:695–698.
- Cordon-Cardo C, O’Brien JP, Boccia J, Casals D, Bertino JR, Melamed MR: Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990;38:1277–1287.
- Sugawara I, Kataoka I, Morishita Y, Hamada H, Tsuruo T, Itoyama S, Mori S: Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res 1988;48:1926–1929.
- Fromm MF: Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci 2004;25:423–429.
- 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 HP: Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994;77:491–502.
- Schinkel AH, Wagenaar E, van Deemter L, Mol CAA, 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;96:1698–1705.
- Callaghan R, Riordan JR: Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J Biol Chem 1993;268:16059–16064.
- Bouer R, Barthe L, Philibert C, Tournaire C, Woodley J, Houin G: The roles of P-glycoprotein and intracellullar metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac. Fundam Clin Pharmacol 1999;13:494–500.
- Nanovskaya T, Nekhayeva I, Karunaratne N, Audus K, Hankins GD, Ahmed MS: Role of P-glycoprotein in transplacental transfer of methadone. Biochem Pharmacol 2005;69:1869–1878.
- Störmer E, Perloff MD, von Moltke LL, Greenblatt DJ: Methadone inhibits rhodamine123 transport in caco-2 cells. Drug Metab Dispos 2001;29:954–956.
- Thompson SJ, Koszdin K, Bernards CM: Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000;92:1392–1399.
- 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 2004;173:132–138.
- 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;56:367–374.
- 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;23:423–430.
- Widmer N, Colombo S, Buclin T, Decosterd LA: Functional consequence of MDR1 expression on imatinib intracellular concentrations. Blood 2003;102:1142.
- Crettol S, Déglon JJ, Besson J, Croquette-Krokkar M, Gothuey I, Hämmig R, Monnat M, Hüttemann H, Baumann P, Eap CB: Methadone enantiomer plasma levels, CYP2B6, CYP2C19 and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 2005;78:593–604.
- Bertschy G, Baumann P, Eap CB, Baettig D: Probable metabolic interaction between methadone and fluvoxamine in addict patients. Ther Drug Monit 1994;16:42–45.
- Eap CB, Bouchoux G, Scherbaum N, Gastpar M, Powell GK, Baumann P: Determination of human plasma levels of levo-alpha-acetylmethadol and its metabolites by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2004;805:141–146.
- Ford JM: Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur J Cancer 1996;32A:991–1001.
- Luurtsema G, Molthoff CF, Windhorst AD, Smit JW, Keizer H, Boellaard R, Lammertsma AA, Franssen EJ: (R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function: in vitro and in vivo evaluation. Nucl Med Biol 2003;30:747–751.
- Barraud de Lagerie S, Comets E, Gautrand C, Fernandez C, Auchere D, Singlas E, Mentre F, Gimenez F: Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice. Br J Pharmacol 2004;141:1214–1222.
- Neuhoff S, Langguth P, Dressler C, Andersson TB, Regardh CG, Spahn-Langguth H: Affinities at the verapamil binding site of MDR1-encoded P-glycoprotein: drugs and analogs, stereoisomers and metabolites. Int J Clin Pharmacol Ther 2000;38:168–179.
- Kharasch ED, Hoffer C, Whittington D: The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br J Clin Pharmacol 2004;57:600–610.
- 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.
- Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U: Functional polymorphisms of the human multidrug-resistant gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473–3478.
- Lötsch J, Skarke C, Wieting J, Oertel BG, Schmidt H, Brockmöller J, Geisslinger G: 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.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.