title: Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients.
abstract: We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) as a marker for CYP3A induction. Plasma 4β-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4β-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4β-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4β-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.
authors.affiliation: 1] Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge C1-68, Stockholm, Sweden [2] Department of Pharmacology, Medical Faculty, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: A
authors.initials: A
authors.lastname: Habtewold
authors.forename: W
authors.initials: W
authors.lastname: Amogne
authors.forename: E
authors.initials: E
authors.lastname: Makonnen
authors.forename: G
authors.initials: G
authors.lastname: Yimer
authors.forename: H
authors.initials: H
authors.lastname: Nylén
authors.forename: K-D
authors.initials: KD
authors.lastname: Riedel
authors.forename: G
authors.initials: G
authors.lastname: Aderaye
authors.forename: L
authors.initials: L
authors.lastname: Bertilsson
authors.forename: J
authors.initials: J
authors.lastname: Burhenne
authors.forename: U
authors.initials: U
authors.lastname: Diczfalusy
authors.forename: E
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000627:therapeutic use*; D003521:Cyclopropanes; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008297:Male; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz