CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

Abstract

We investigated the effect of efavirenz on the activities of cytochrome P450 (CYP)1A2, CYP2A6, xanthine oxidase (XO), and N‐acetyltransferase 2 (NAT2), using caffeine as a probe. A single 150 mg oral dose of caffeine was administered to healthy volunteers (n = 58) on two separate occasions; with a single 600 mg oral dose of efavirenz and after treatment with 600 mg/day efavirenz for 17 days. Caffeine and its metabolites in plasma and urine were quantified using liquid chromatography/tandem‐mass spectrometry. DNA was genotyped for CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), and CYP2B6*18 (983T>C) alleles using TaqMan assays. Relative to single‐dose efavirenz treatment, multiple doses of efavirenz decreased CYP1A2 (by 38%) and increased CYP2A6 (by 85%) activities (P < 0.05); XO and NAT2 activities were unaffected. CYP2B6*6*6 genotype was associated with lower CYP1A2 activity following both single and multiple doses of efavirenz. No similar association was noted for CYP2A6 activity. This is the first report showing that efavirenz reduces hepatic CYP1A2 and suggesting chronic efavirenz exposure likely enhances the elimination of CYP2A6 substrates. This is also the first to report the extent of efavirenz–CYP1A2 interaction may be efavirenz exposure‐dependent and CYP2B6 genotype‐dependent.

Inhibition and induction of CYP enzymes in humans: an update

“…(minor effect at most) Minor effect in vitro at most 2C9? Lee et al ( 2012 ), Tseng et al ( 2017 ) Raltegravir E: major M: UGT1A, no CYPs No significant effects No in vitro/in vivo No in vitro/in vivo Okeke and Hicks ( 2011 ) Non-nucleoside reverse transcriptase inhibitors Doravirine M: 3A4 Strong 3A4 inhibitors ritonavir, ketoconazole (moderate) Strong 3A4 inducers rifampicin (strong) No in vitro/in vivo NA In vivo 3A4 (weak) Khalilieh et al ( 2019 ) Efavirenz M: 2B6 (primary), 2A6, 3A4 2B6 and 3A4-inducers and inhibitors (variable observed or predicted effects) 2C9, 2C19, 3A4 In vivo variable effects 3A4, 2B6 in vitro 2B6 autoinduction 2A6, 2B6, 2C19, 3A4 in vivo variable effects Best and Goicoechea ( 2008 ), Marzolini et al ( 2017 ), McDonagh et al ( 2015 ), Metzger et al ( 2019 ) Etravirine M: 3A4, 2C9, 2C19 Inhibitors and inducers variable effects 2C9, 2C19 In vitro variable effects 3A4 Havens et al ( 2020 ) Nevirapine M: 3A4, 2B6 Rifampicin (moderate) Fluconazole (strong) 3A4, 2B6 (both weak) Weak or no effects in vitro or in vivo 3A4, 2B6 In vivo autoinduction In vivo weak or moderate effect at most Ena et al ( 2012 ) Rilp...…”

“… Liver (phenotyping) Paladino et al ( 1983 ) Immunosuppressants Teriflunomide CAR? Liver (phenotyping) Aubagio summary of product characteristics a Proton pump inhibitors Omeprazole AHR Liver (phenotyping and expression) Diaz et al ( 1990 ), Rost et al ( 1994 ), Rost and Roots ( 1994 ) CYP2A6 Antiepileptics Carbamazepine CAR/PXR Liver (phenotyping and expression) Oscarson et al ( 2006 ), Williams et al ( 2010 ) Antimalarials Artemisinin CAR/PXR Liver (phenotyping) Asimus et al ( 2008 ) Antiretrovirals Efavirenz CAR/PXR Liver (phenotyping) Metzger et al ( 2019 ) Barbiturates Phenobarbital CAR/PXR Liver (expression) Cashman et al ( 1992 ), Kyerematen et al ( 1990 ), Yamano et al ( 1990 ) Estrogens Ethinyl estradiol (of oral contraceptives) ER Liver (phenotyping) Benowitz et al ( 2006 ), Berlin et al ( 2007 ), Sinues et al ( 2008 ) CYP2B6 Antibiotics Rifampicin PXR …”

Clinically relevant enantiomer specific R‐ and S‐praziquantel pharmacokinetic drug‐drug interactions with efavirenz and ritonavir

“…Efavirenz also has an inhibitory effect on CYP2C19 and CYP1A2. 19 We therefore evaluated the extent and nature of the risk of drug-drug interactions in the co-treatment of HIV and schistosomiasis in this study. The aim is to increase knowledge towards the safe and efficacious use of PZQ especially in cases of coinfection and in mass drug treatment programs where the HIV status of an individual and concomitant drugs have not been taken into consideration before PZQ administration.…”

“…We, therefore, hypothesize that there will be a greater inhibitory and induction effect on S‐PZQ as compared to the R‐isoform since efavirenz and ritonavir have been shown to induce and inhibit CYP3A. Efavirenz also has an inhibitory effect on CYP2C19 and CYP1A2 19 . We therefore evaluated the extent and nature of the risk of drug‐drug interactions in the co‐treatment of HIV and schistosomiasis in this study.…”

“…16,17 These enzymes are modulated by inducers and inhibitors. Among the ARVs, efavirenz is a known inducer of CYP3A and CYP2C19 18 and inhibitor of CYP1A2 19 and CYP2C19. 20 Protease inhibitors are known potent inhibitors of CYP3A and CYP2C19.…”