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Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans.
- Source :
-
The Journal of infectious diseases [J Infect Dis] 2009 Mar 15; Vol. 199 (6), pp. 872-80. - Publication Year :
- 2009
-
Abstract
- Background: Polymorphisms in CYP2B6 affect the steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, a single dose of nevirapine has been widely prescribed to pregnant women at delivery, to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). We characterized associations between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz.<br />Methods: Plasma drug concentrations were determined over the 13-day period after administration of a 200-mg oral dose of nevirapine to nonpregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered, and pharmacokinetic sampling was repeated. Pharmacokinetic parameters were estimated using a noncompartmental approach. Primary analyses involved 2 CYP2B6 polymorphisms (516G --> T and 983T --> C) known to predict increased steady-state plasma nevirapine and efavirenz exposure. Exploratory analyses involved another 51 polymorphisms in CYP2B6, ABCB1, CYP3A4, and CYP3A5.<br />Results: On the basis of the composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. The composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and the pharmacokinetics of nevirapine and efavirenz.<br />Conclusions: Selective pressure for drug-resistant HIV-1 after administration of single-dose nevirapine may not differ substantially according to CYP2B6 516/983 genotype. Additional polymorphisms, genes, and populations warrant further study.
- Subjects :
- Alkynes
Anti-HIV Agents blood
Anti-HIV Agents pharmacology
Area Under Curve
Benzoxazines blood
Benzoxazines pharmacology
Cyclopropanes
Cytochrome P-450 CYP2B6
Genotype
HIV Seronegativity
Humans
Linkage Disequilibrium
Metabolic Clearance Rate
Nevirapine blood
Nevirapine pharmacology
Safety
Black or African American
Anti-HIV Agents pharmacokinetics
Aryl Hydrocarbon Hydroxylases genetics
Aryl Hydrocarbon Hydroxylases pharmacokinetics
Benzoxazines pharmacokinetics
Black People genetics
Nevirapine pharmacokinetics
Oxidoreductases, N-Demethylating genetics
Oxidoreductases, N-Demethylating pharmacokinetics
Polymorphism, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1899
- Volume :
- 199
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 19239339
- Full Text :
- https://doi.org/10.1086/597125