Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
1.
Pharmacogenomics J ; 13(6): 484-9, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23089673

ABSTRACT

We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4ß-hydroxycholesterol/cholesterol (4ß-OHC/Chol) as a marker for CYP3A induction. Plasma 4ß-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 4ß-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4ß-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 4ß-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.


Subject(s)
Benzoxazines/therapeutic use , Cytochrome P-450 CYP3A/biosynthesis , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/therapeutic use , Alkynes , Cyclopropanes , Cytochrome P-450 CYP3A/genetics , Enzyme Induction , Female , HIV Infections/enzymology , Humans , Male , Prospective Studies
2.
Pharmacogenomics J ; 12(6): 499-506, 2012 Dec.
Article in English | MEDLINE | ID: mdl-21862974

ABSTRACT

The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) drug-induced liver injury (DILI). ART-naïve HIV patients (n = 285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography-mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P = 0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P = 0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.


Subject(s)
Antiretroviral Therapy, Highly Active/adverse effects , Aryl Hydrocarbon Hydroxylases/genetics , Benzoxazines/adverse effects , Chemical and Drug Induced Liver Injury/genetics , HIV Infections/drug therapy , Oxidoreductases, N-Demethylating/genetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Adult , Alkynes , Benzoxazines/blood , Cohort Studies , Cyclopropanes , Cytochrome P-450 CYP2B6 , Cytochrome P-450 CYP3A/genetics , Female , Genotype , Humans , Male , Proportional Hazards Models , Prospective Studies
SELECTION OF CITATIONS
SEARCH DETAIL
...