Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry

Wang, Pan-Fen; Neiner, Alicia; Kharasch, Evan D.

doi:10.1124/dmd.119.086348

Cited by 29 publications

(25 citation statements)

References 67 publications

(153 reference statements)

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“…Table 2). (Ahmad et al, 2017;Binnington et al, 2012;Bloom et al, 2019;Bloom, Harari, et al, 2013;Bloom, Martinez, et al, 2013;Desta et , 2002;Fernandez-Salguero et al, 1995;Gervot et al, 1999;Hulot et al, 2006;Pianezza et al, 1998;Pitarque et al, 2001;Sim et al, 2006;Wang et al, 2019)]. Highprevalence functional alleles (MAF>0.05) are not observed for CYP3A4 (Eiselt et al, 2001;Zhou et al, 2017).…”

Section: Uhplc-ms/ms Analysis Uhplc-ms/ms Was Performed On a Uplc-beh-mentioning

confidence: 99%

CYP2C19 Plays a Major Role in the HepaticN-Oxidation of Cotinine

et al. 2022

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The primary mode of metabolism of nicotine is via the formation of cotinine by the enzyme CYP2A6. Cotinine undergoes further CYP2A6-mediated metabolism by hydroxylation to 3-hydroxycotinine and norcotinine, but can also form cotinine- N -glucuronide and cotinine- N -oxide (COX). The goal of this study was to investigate the enzymes that catalyze COX formation and determine whether genetic variation in these enzymes may affect this pathway. Specific inhibitors of major hepatic cytochrome P450 (P450) enzymes were used in cotinine- N -oxidation reactions using pooled human liver microsomes (HLMs). COX formation was monitored by ultrahigh-pressure liquid chromatography–tandem mass spectrometry and enzyme kinetic analysis was performed using microsomes from P450-overexpressing human embryonic kidney 293 (HEK293) cell lines. Genotype-phenotype analysis was performed in a panel of 113 human liver specimens. Inhibition of COX formation was only observed in HLMs when using inhibitors of CYP2A6, CYP2B6, CYP2C19, CYP2E1, and CYP3A4. Microsomes from cells overexpressing CYP2A6 or CYP2C19 exhibited similar N -oxidation activity against cotinine, with maximum reaction rate over Michaelis constant values (intrinsic clearance) of 4.4 and 4.2 nL/min/mg, respectively. CYP2B6-, CYP2E1-, and CYP3A4-overexpressing microsomes were also active in COX formation. Significant associations ( P < 0.05) were observed between COX formation and genetic variants in CYP2C19 (*2 and *17 alleles) in HLMs. These results demonstrate that genetic variants in CYP2C19 are associated with decreased COX formation, potentially affecting the relative levels of cotinine in the plasma or urine of smokers and ultimately affecting recommended smoking cessation therapies. SIGNIFICANCE STATEMENT This study is the first to elucidate the enzymes responsible for cotinine- N -oxide formation and genetic variants that affect this biological pathway. Genetic variants in CYP2C19 have the potential to modify nicotine metabolic ratio in smokers and could affect pharmacotherapeutic decisions for smoking cessation treatments.

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Section: Uhplc-ms/ms Analysis Uhplc-ms/ms Was Performed On a Uplc-beh-mentioning

confidence: 99%

CYP2C19 Plays a Major Role in the HepaticN-Oxidation of Cotinine

et al. 2022

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“…Regarding the metabolism of efavirenz, it should be noted that in the present study only plasma concentrations of the parent drug were determined, as drug elimination was not a focus of this study. Furthermore, the metabolites (mainly 8-hydroxy-efavirenz through CYP2B6 but also 7-hydroxy-efavirenz through CYP2A6 [ 36 ]) are not relevant pharmacologically [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Particle Forming Amorphous Solid Dispersions: A Mechanistic Randomized Pharmacokinetic Study in Humans

et al. 2021

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Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof (AUC0–t, Cmax, tmax, and ka). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar AUC0–t and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models.

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“…It had moderately decreased activity in S-efavirenz hydroxylation and slightly increased activity in R-efavirenz hydroxylation . CYP2B6.9 (516G>T, Q172H) was substantially less active than CYP2B6.1 in bupropion metabolism, as well as methadone, ketamine, efavarenz, and nicotine, and moderately less (30%) with artemether, but more active than CYP2B6.1 in ifosfamide bioactivation (Honda et al, 2011;Calinski et al, 2015;Gadel et al, 2015;Wang et al, 2018;Bloom et al, 2019;Wang et al, 2019). CYP2B6.6 (516G>T-785A>G, Q172H-K262R) has been studied extensively in vitro and in vivo due to its high frequency of occurrence and therapeutic significance.…”

Section: Discussionmentioning

confidence: 99%

“…CYP2B6.6 (516G>T-785A>G, Q172H-K262R) has been studied extensively in vitro and in vivo due to its high frequency of occurrence and therapeutic significance. CYP2B6.6 was less active than wild-type in metabolism of bupropion, as well as methadone, ketamine, efavirenz, bupropion, ifosfamide, and nicotine, but more active in metabolizing cyclophosphamide and artemether (Ariyoshi et al, 2011;Honda et al, 2011;Calinski et al, 2015;Gadel et al, 2015;Wang et al, 2018;Bloom et al, 2019;Wang et al, 2019). CYP2B6.16 and CYP2B6.18, which were essentially inactive towards buproiopion, are also inactive with methadone, ketamine, and efavirenz (Gadel et al, 2015;Wang et al, 2018;Wang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Stereoselective Bupropion Hydroxylation by Cytochrome P450 CYP2B6 and Cytochrome P450 Oxidoreductase Genetic Variants

2020

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Bioactivation of the antidepressant and smoking cessation drug bupropion is catalyzed predominantly by cytochrome P4502B6 (CYP2B6). The metabolite hydroxybupropion derived from t-butylhydroxylation is considered to contribute to the antidepressant and smoking-cessation effects of the parent drug.Bupropion hydroxylation is the canonical in vitro and in vivo probe for CYP2B6 activity. P450 also requires obligate partnership with P450 oxidoreductase (POR). Human CYP2B6 and POR genes are highly polymorphic. Some CYP2B6 variants affect bupropion disposition. This investigation evaluated the influence of several human CYP2B6 and POR genetic variants on stereoselective bupropion metabolism, using an insect cell coexpression system containing CYP2B6, POR and cytochrome b 5 .Based on intrinsic clearances, relative activities for S,S-hydroxybupropion formation were in the order CYP2B6.4>CYP2B6.1>CYP2B6.17>CYP2B6.5>CYP2B6.6≈CYP2B6.26≈CYP2B6.19>CYP2B6.7> CYP2B6.9>>CYP2B6.16 and CYP2B6.18; relative activities for R,R-hydroxybupropion formation were in the order CYP2B6.17>CYP2B6.4>CYP2B6.1>CYP2B6.5≈CYP2B6.19≈CYP2B6.26>CYP2B6.6> CYP2B6.7≈ CYP2B6.9>>CYP2B6.16 and CYP2B6.18. Bupropion hydroxylation was not influenced by POR variants. CYP2B6-catalyzed bupropion hydroxylation is stereoselective. Though V max and K m varied widely among CYP2B6 variants, stereoselectivity was preserved, reflected by similar Cl int (S,Shydroxybupropion)/Cl int (R,R-hydroxybupropion) ratios (1.8 to 2.9), except CYP2B6.17, which was less enantioselective. Established concordance between human bupropion hydroxylation in vitro and in vivo, together with these new results, suggests additional CYP2B6 variants may influence human bupropion disposition.

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Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry

Cited by 29 publications

References 67 publications

CYP2C19 Plays a Major Role in the HepaticN-Oxidation of Cotinine

CYP2C19 Plays a Major Role in the HepaticN-Oxidation of Cotinine

Particle Forming Amorphous Solid Dispersions: A Mechanistic Randomized Pharmacokinetic Study in Humans

Stereoselective Bupropion Hydroxylation by Cytochrome P450 CYP2B6 and Cytochrome P450 Oxidoreductase Genetic Variants

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