title: Genetic variations in ABCB1 and CYP3A5 as well as sex influence quinine disposition among Ugandans.
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 mumol/L; range, 0.88-18.10 mumol/L) and quinine-to-3-hydroxyquinine metabolic ratio (mean +/- standard deviation, 7.68 +/- 3.3 mumol/L; range, 1.66-22.3 mumol/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.
authors.affiliation: Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
authors.forename: Jackson K
authors.initials: JK
authors.lastname: Mukonzo
authors.forename: Paul
authors.initials: P
authors.lastname: Waako
authors.forename: Jasper
authors.initials: J
authors.lastname: Ogwal-Okeng
authors.forename: Lars L
authors.initials: LL
authors.lastname: Gustafsson
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D044383:Black People; D001835:Body Weight; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D005260:Female; D005796:Genes / Q000502:physiology; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D011110:Polymorphism, Genetic / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011802:Quinidine / Q000031:analogs & derivatives* / Q000378:metabolism; D011803:Quinine / Q000378:metabolism* / Q000494:pharmacology; D012737:Sex Factors; D014454:Uganda
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D007166:Immunosuppressive Agents; C013569:3-hydroxyquinidine; D011803:Quinine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine