Open AccessEffects of Tuberculosis, Race, and Human Gene SLCO1B1 Polymorphisms on Rifampin Concentrations
Author(s) -
Marc Weiner,
Charles A. Peloquin,
William J. Burman,
Chi Cheng Luo,
Melissa Engle,
Thomas J. Prihoda,
William R. Mac Kenzie,
Erin Bliven-Sizemore,
John L. Johnson,
Andrew Ver
Publication year - 2010
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00353-10
Subject(s) - slco1b1 , tuberculosis , pharmacokinetics , mycobacterium tuberculosis , rifampicin , genotype , medicine , area under the curve , single nucleotide polymorphism , biology , pharmacology , gene , genetics , pathology
Rifampin has concentration-dependent activity againstMycobacterium tuberculosis . However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genesSLCO1B1 ,SLCO1B3 , andMDR1 . Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC0-24 ] of 40.2 versus 40.9 μg·h/ml;P = 0.9). However, in multivariable analyses, the rifampin AUC0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in theSLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC0-24 was also 36% lower among participants withSLCO1B1 genotype c.463CA than that among participants withSLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml;P = 0.001). Polymorphisms in theSLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC0-24 values was observed, but the mean values of the AUC0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of theSLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.