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Stereo-Selective Metabolism of Methadone by Human Liver Microsomes and cDNA-Expressed Cytochrome P450s: A Reconciliation
- Source :
- Basic & Clinical Pharmacology & Toxicology. 108:55-62
- Publication Year :
- 2010
- Publisher :
- Wiley, 2010.
-
Abstract
- Methadone is a μ-opioid receptor agonist that is used for the treatment of chronic pain and opioid dependence. Clinically it is used in the racemic form; (R)-methadone has higher affinity at μ and δ opioid receptors [1] and greater analgesic activity [2]. Pharmacokinetic studies in humans have also found differences between the two isomers, with (R)-methadone having significantly longer elimination half-life, greater volume of distribution, and lower protein binding [3–5]. Methadone is subject to numerous pharmacokinetic drug interactions; these are thought to primarily occur at cytochrome P450 (CYP) sites of methadone metabolism [6–9]. The stereo-selectivity of the drug interaction may be of importance; interactions that increase or decrease (R)-methadone may lead to toxicity (i.e. respiratory depression) or withdrawal, respectively; interactions that increase (S)-methadone may increase the incidence of prolonged QT intervals [10]. Since the initial studies on CYP involvement in the in vitro metabolism of methadone [11,12], five other laboratories have investigated comparative involvement of different CYPs in methadone metabolism [13–19]. Most of these in vitro studies focused on the predominant metabolic pathway, N-demethylation followed by spontaneous cyclization to form 2-ethyl-1,5-dimethyl-3,3,-diphenylpyrrolidine (EDDP). The involvement of CYP3A4 was noted in all of these studies; and all that studied stereo-selectivity noted none for 3A4-mediated methadone N-demethylation [13,15,16,18,19]. Two laboratories also studied methadone depletion, with contrasting results; Wang and De Vane [15] found CYP3A4 depleted (R)-methadone at a much higher rate, Gerber et al. [16] found no difference in the depletion of (R)- and (S)-methadone by CYP3A4. As tools to study CYP2B6 became available, its important role in methadone N-demethylation was also noted [16,17], and studies on the stereo-selectivity of the reaction consistently showed higher rates of (S)-methadone metabolism by CYP2B6 [16,18,19]. Other CYPs have also been reported to be involved in methadone N-demethylation including: 2D6 [11,15,16], 2C8 [15], 2C9 [11–13,16] and 2C19 [11,13,16,18,19]. Among these CYPs, 2C19 (R > S) [16,18,19], 2C8 (R > S) and 2D6 (S > R) [15] displayed stereo-selectivity. These studies leave some questions about the involvement of CYPs besides 3A4 and 2B6 in methadone N-demethylation and the stereo-selectivity of methadone depletion. Only one study on CYP2B6 stereo-selective methadone N-demethylation provided detailed evidence beyond metabolism in recombinant expressed CYP [19]. The current investigation has both confirmed and expanded on these findings. We have tested the stereo-selective metabolism of methadone in a large panel of CYP Supersomes with scaling of Supersome activities, correlation analysis and use of a number of specific chemical inhibitors and monoclonal antibodies. The relative contribution of 3A4 and 2B6, as well as other CYPs, to in vitro methadone metabolism and stereo-selective metabolism was determined.
Details
- ISSN :
- 17427835
- Volume :
- 108
- Database :
- OpenAIRE
- Journal :
- Basic & Clinical Pharmacology & Toxicology
- Accession number :
- edsair.doi...........176da2f1b3e7931222a9dcbb8c23b130