Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study

Purpose: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. Methods: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. Results: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. Conclusion: Cannabis use and higher methadone doses in MMT could in part be a response to—or a cause of—more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MM

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone

Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizer: evidence of a safer cardiac profile of (R)-methadone

Methadone is widely prescribed (about 215'000 opioid dependent patients and >275'000 patients treated for pain in the US, and about 150'000 subjects in methadone maintenance therapy in the EU). Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval, with several described cases of torsades de pointes and sudden deaths. Methadone is chiral but its therapeutic (opioid) activity is mainly due to (R)-methadone. Using whole-cell patch-clamp experiments using cells expressing hERG, we showed, that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s at 37°C: 2 and 7µM; Eap et al., Clin Pharmacol Ther 81:719-28, 2007). In addition, as CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone (Crettol et al. Clin Pharmacol Ther, 78(6) :593-604, 2005), electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone (Eap et al., Clin Pharmacol Ther 81:719-28, 2007). The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 43925ms; n=11) than in extensive metabolizers (non *6/*6; 42125ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports a stereoselectivity in the hERG channel blockade and a potential safer cardiac profile of (R)-methadone. In addition, it reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. The prescription of the pure enantiomer would therefore reduce the risk of cardiac toxicity and sudden death in the very large number of patients treated with methadone worldwide. Interestingly, our studies also suggests that stereoselectivity in the hERG current blockade should be more often considered in the field of drug-induced prolonged QT interval which, in addition to methadone, could lead to the finding of other, safer drugs

Polytoxicomanie et médecin praticien [dossier]

Ce dossier contient : p. 871-874: Polytoxicomanie : quelle place pour les traitements de substitution? / I. Gothuey . - p. 875-879: La cocaïne : état des lieux / P. Sanchez-Mazas - p. 881-884: Benzodiazépines et abus de substances / B. Broers, J.-P. Voegli. - p. 885-888: Les nouvelles drogues : ecstasy, GHB : une mise au point pour les praticiens / N. Feldman, M. Croquette-Krokar. - p. 889-893: Dépendance : tous semblables, tous différents : point de vue d'un praticien, point de vue d'un spécialiste / F. Pilet, J. Besson. - p. 895-897 : Prise en charge des aptients avec des problèmes d'alcool : quelle efficacité? : quelques éléments de réponse à partir d'une revue de la littérature / B. Graz, J. Cornuz, J.-B Daeppen. - p. 903-906: La buprénorphine / C. Uehlinger - p. 907-910: Consommation d'alcool chez les toxicomanes : l'alcool est-il un moindre mal? / R. Gammeter, J.-B. Daeppe

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study

Purpose: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. Methods: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. Results: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14–16% and 17–25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. Conclusion: Cannabis use and higher methadone doses in MMT could in part be a response to—or a cause of—more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.Richard Hallinan, Séverine Crettol, Kingsley Agho, John Attia, Jacques Besson, Marina Croquette-Krokar, Robert Hämmig, Jean-Jacques Déglon, Andrew Byrne, John Ray, Andrew A. Somogyi, Chin B. Ea