Rifampin has concentration-dependent activity against Mycobacterium 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 genes SLCO1B1, SLCO1B3, and MDR1. 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 [AUC 0-24 ] of 40.2 versus 40.9 g ⅐ h/ml; P ‫؍‬ 0.9). However, in multivariable analyses, the rifampin AUC 0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC 0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC 0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 g ⅐ h/ml; P ‫؍‬ 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC 0-24 values was observed, but the mean values of the AUC 0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 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.

Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters. This was a single-center, sequential design study with 16 volunteers in which sampling was performed after four daily oral doses of moxifloxacin (400 mg) and again after 10 days of combined rifampin (600 mg) and moxifloxacin. There is increasing interest in the possible role of newer fluoroquinolone antibiotics in the treatment of drug-susceptible tuberculosis. In a murine model of tuberculosis treatment, the substitution of moxifloxacin for isoniazid allows treatment to be shortened from 6 months to 4 months (10). Moxifloxacincontaining regimens are currently being evaluated in phase II treatment trials (1; Tuberculosis Trials Consortium Study 28). Moxifloxacin undergoes phase II biotransformation by two pathways: (i) sulfate conjugation, with the resultant metabolite (M1 conjugate) accounting for 38% of an oral dose of moxifloxacin, and (ii) glucuronide conjugation, with the resultant metabolite (M2 conjugate) accounting for 14% of an oral dose (16). The CYP450 system does not play a role in moxifloxacin metabolism. Although best known for its effects on the CYP450 system, rifampin can also up-regulate the phase II metabolic glucuronidation pathway (5).P-glycoprotein is a protein found in the intestinal mucosa, liver, and kidney that plays an important role in the absorption, distribution, and elimination of xenobiotics (8). The multidrug resistance gene (MDR1) codes for P-glycoprotein, and polymorphisms in the MDR1 gene can lead to altered P-glycoprotein function. For example, subjects homozygous for the MDR1 C3435T polymorphism had lower intestinal P-glycoprotein concentrations and higher plasma digoxin concentrations (6, 7). P-glycoprotein is induced by rifampin (9, 12). This observation suggests another possible mechanism for a rifampin-induced drug-drug interaction. We evaluated the effects of rifampin and MDR1 C3435T polymorphisms on the pharmacokinetics of moxifloxacin.The primary objective of the study was to compare the pharmacokinetics of daily moxifloxacin without and with coadministration of rifampin. A secondary objective was to characterize the effects of MDR1 C3435T polymorphisms on moxifloxacin pharmacokinetics.(Some of the results of this study have been reported previously in abstract form [18]). MATERIALS AND METHODSExperimental design. This was a single-center, two-period, open-label, sequential-design pharmacokinetic study. The first pharmacokinetic sampling was performed with the fourth daily dose of oral moxifloxacin (400 mg once daily). Rifampin (600 mg once-daily, given at the same time as moxifloxacin) was then added, and a second sampling was performed with the 10th dose of rifampin (the 14th dose of daily moxifloxacin). The st...