Increase of R-/S-Methadone Enantiomer Concentration Ratio in Serum of Patients Treated with Either Nevirapine or Efavirenz

Esteban, Javier; Pellín, María de la Cruz; Gimeno, Carmen; Barril, J.; Giménez, Jesús; Mora, Eva; García-Pérez, Adolfo

doi:10.2174/187231208786734067

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…Together, these observations indicate that stereoselective decreases in methadone plasma concentrations result from preferential induction of hepatic S‐methadone N ‐demethylation, hepatic clearance, and systemic clearance. An additional consequence of stereoselective induction by efavirenz was an enhanced R/S‐methadone plasma concentration ratio, as reported previously 54 …”

Section: Discussionsupporting

confidence: 78%

Mechanism of Efavirenz Influence on Methadone Pharmacokinetics and Pharmacodynamics

Kharasch

Whittington

Ensign

et al. 2012

Clin Pharmacol Ther

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Efavirenz diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but actual mechanisms are unknown. This investigation determined the effects of two weeks of efavirenz (600 mg daily) on hepatic and intestinal CYP3A4/5 (probed with intravenous and oral alfentanil), hepatic CYP2B6 (oral efavirenz hydroxylation) and intestinal transporter (oral fexofenadine) activities, and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. It also assessed efavirenz effects on CYP expression and activity in human hepatocytes. Efavirenz significantly induced systemic and oral alfentanil clearance 2- to 5-fold, increased alfentanil hepatic and intestinal extraction ratios, and significantly induced apparent 8-hydroxyefavirenz formation clearance. Efavirenz also moderately decreased fexofenadine plasma concentrations, suggesting decreased intestinal uptake and/or increased P-glycoprotein-mediated efflux. Efavirenz induced CYP2B6 and CYP3A4 expression, activity, and methadone metabolism in human hepatocytes. Efavirenz coinduces hepatic CYP2B6 and CYP3A4/5 activities, coinduces hepatic and intestinal CYP3A4/5, and coinduces gastrointestinal CYP3A and xenobiotic efflux transporters.

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Section: Discussionsupporting

confidence: 78%

Mechanism of Efavirenz Influence on Methadone Pharmacokinetics and Pharmacodynamics

Kharasch

Whittington

Ensign

et al. 2012

Clin Pharmacol Ther

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“…Through activation of the nuclear receptor constitutive androstane receptor (CAR), efavirenz strongly influences the expression of several CYPs and transporters. Of particular importance here, CYP2B6 and CYP3A4 activity are induced up to several fold and interactions with CYP3A4 and CYP2B6 substrates have been confirmed in several clinical studies (Esteban et al 2008 ; Faucette et al 2007 ; Mouly et al 2002 ).…”

Section: Resultsmentioning

confidence: 65%

Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz

Siccardi

Olagunju

Seden

et al. 2013

In Silico Pharmacol.

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PurposeTo treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design.MethodsIn vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600 mg once daily) was administered to 50 virtual subjects for 14 days. This was followed by concomitant administration of artemether (80 mg eight hourly) for the first two doses and 80 mg (twice daily) for another two days.ResultsSimulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether Cmax by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240 mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether.ConclusionsThe model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition.

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“…Cyclodextrins (CDs) additives have mostly been used in the enantioselective separation of MTD and/or EDDP. CDs including heptakis-(2,6-di-O-methyl)-␤-cyclodextrin (DM-␤-CD) [26,28], (2-hydroxylpropyl)-␤-cyclodextrin (HP-␤-CD) [24,[29][30][31], carboxylmethyl-␤-cyclodextrin [31][32][33], highly sulphated ␤-cyclodextrin (HS-␤-CD) [34] and sulphobutyl ether-␤-cyclodextrin [31] have been applied for the chiral separation of MTD and/or EDDP in urine, plasma or hair. Recently, Rudaz et al [35] obtained optimal resolution of methanolic solutions of racemic MTD by CE/MS using highly sulphated gamma cyclodextrin (HS-␥-CD) as chiral selector.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous enantioselective quantification of methadone and of 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine in oral fluid using capillary electrophoresis

Martins

Yegles

Wennig

2008

Journal of Chromatography B

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Increase of R-/S-Methadone Enantiomer Concentration Ratio in Serum of Patients Treated with Either Nevirapine or Efavirenz

Cited by 8 publications

References 28 publications

Mechanism of Efavirenz Influence on Methadone Pharmacokinetics and Pharmacodynamics

Mechanism of Efavirenz Influence on Methadone Pharmacokinetics and Pharmacodynamics

Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz

Simultaneous enantioselective quantification of methadone and of 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine in oral fluid using capillary electrophoresis

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