Author:
Chigutsa Emmanuel,Visser Marianne E.,Swart Elizabeth C.,Denti Paolo,Pushpakom Sudeep,Egan Deirdre,Holford Nicholas H. G.,Smith Peter J.,Maartens Gary,Owen Andrew,McIlleron Helen
Abstract
ABSTRACTAmong 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 theABCB1gene) and organic anion-transporting polypeptide 1B1 (coded for bySLCO1B1). 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 forABCB1,SLCO1B1,PXR, andCARpolymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of theSLCO1B1rs4149032 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 (Cmax) below 8 mg/liter from 63% to 31%.ABCB1,PXR, andCARpolymorphisms were not associated with differences in rifampin pharmacokinetics.SLCO1B1rs4149032 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
126 articles.
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