School of Bio-Medical Sciences (Bio-Medical) Collections

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Browsing School of Bio-Medical Sciences (Bio-Medical) Collections by Subject "ABCB1"
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    Genetic variations in ABCB1 and CYP3A5 as well as sex influence quinine disposition among Ugandans
    (Lippincott Wilkins & Williams, 2010) Mukonzo, Jackson K ; Waako, Paul ; Ogwal-Okeng, Jasper ; Gustafsson, Lars L. ; Aklillu, Eleni
    Abstract: Quinine is one of the most effective antimalarial drugs, although its clinical use is limited as a result of its narrow safety margin. Quinine is a substrate of the polymorphic p-glycoprotein and CYP3A4/3A5. This study aimed to examine the effects of genetic variations in ABCB1 and CYP3A5 genes, sex, demographic, and biochemical variables (serum albumin, creatinine, alanine aminotransferase and albumin) on quinine disposition among Ugandans. Quinine (600 mg) was orally administered to 140 healthy volunteers. Quinine and its metabolite 3-hydroxyquinine concentrations were determined from 16-hour postdose plasma by high-performance liquid chromatography. CYP3A5 activity was measured using quinine/3-hydroxyquinine ratio (metabolic ratio). Genotyping for a total of 20 single nucleotide polymorphisms in ABCB1 (n = 13) and CYP3A5 (n = 7) was done using Taqman and minisequencing on microarray. There were 20.5- and 13-fold variations in body weight adjusted plasma quinine concentrations (mean ± standard deviation, 5.26 ± 2.5 µmol/L; range, 0.88–18.10 µmol/L) and quinine-to-3- hydroxyquinine metabolic ratio (mean ± standard deviation, 7.68 ± 3.3 µmol/L; range, 1.66–22.3 µmol/L), respectively. Weight-adjusted plasma quinine concentration was significantly influenced by sex and ABCB1 haplotype. There was a significant sex difference in quinine metabolic ratio, women being faster metabolizers than men (P = 0.01). CYP3A5 genotype/haplotype significantly (P = 0.03) influenced quinine disposition with a clear CYP3A5*1 gene dose effect. The result confirms that quinine disposition is influenced mainly by sex as well as by ABCB1 and CYP3A5 genotypes. Despite being fast metabolizers, women display higher quinine bioavailability than men in Uganda. This may have clinical significance in determining an individual’s susceptibility to quinine-associated adverse reactions such as cinchonism.
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    A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans
    (The British Pharmacological Society, 2009) Mukonzo, Jackson K ; Röshammar, Daniel ; Waako, Paul ; Andersson, Maria ; Fukasawa, Takashi ; Milani, Lili ; Svensson, Jan Olof ; Ogwal-Okeng, Jasper ; Gustafsson, Lars L. ; Aklillu, Eleni
    AIMS Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS Apparent oral clearance (95% confidence interval) was 4 l h l-1 (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.