title: The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications.
abstract: Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C(max)) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, K-45 Old Main Building, Groote Schuur Hospital, Observatory, 7925 Cape Town, South Africa.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chigutsa
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Visser
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Swart
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.forename: Sudeep
authors.initials: S
authors.lastname: Pushpakom
authors.forename: Deirdre
authors.initials: D
authors.lastname: Egan
authors.forename: Nicholas H G
authors.initials: NH
authors.lastname: Holford
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000097:blood* / Q000627:therapeutic use; D000090702:Constitutive Androstane Receptor; D005260:Female; D005838:Genotype; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D000077297:Pregnane X Receptor; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D012293:Rifampin / Q000097:blood* / Q000627:therapeutic use; D013019:South Africa; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000904:Antibiotics, Antitubercular; D000090702:Constitutive Androstane Receptor; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C503999:SLCO1B1 protein, human; D012293:Rifampin