Effects of Repeated Rifabutin Administration on the Pharmacokinetics of Intravenous and Oral Ciprofloxacin in Mice

Abstract

The combination of rifabutin and ciprofloxacin is potentially useful for the treatment of disseminated Mycobacterium avium-intracellulare (MAC) diseases in HIV-infected patients. Rifabutin is a metabolic enzyme inducer structurally similar to its predecessor, rifampin. Using a mouse model, the effects of repeated exposure of rifabutin on the pharmacokinetics of ciprofloxacin after intravenous (i.v.) and oral (p.o.) dosing were investigated in the present study. Results showed that repeated exposure of rifabutin, relative to control, caused a 16% increase in the plasma clearance (CL) of ciprofloxacin after i.v. dosing (4.19 vs. 4.87 L/h/kg). Estimates of elimination half-life (T1/2) were not affected by rifabutin (control: 0.81 vs. rifabutin pretreated: 1.18 h). The data obtained after oral dosing showed that repeated rifabutin dosing caused a significant reduction in the maximal plasma concentration (Cmax: 1.34 vs. 0.91 μg/mL) and a longer time to Cmax (Tmax: 0.17 vs. 0.33 h). These changes might be in part attributable to the increase in oral clearance (CL/F) by 18%. With or without rifabutin pretreatment, the T1/2 estimates of ciprofloxacin for p.o. dosing were similar (2.37-2.58 h) and were approximately twice as long as those obtained after i.v. dosing. Since the changes in systemic exposure as a result of rifabutin pretreatment were similar after i.v. and p.o. dosing, the oral bioavailability (F) of ciprofloxacin remained unaffected by rifabutin at approximately 38%. The effects of rifabutin on the pharmacokinetics of ciprofloxacin appear to be moderate in the mouse model which might be attributable to the absorption and distribution behavior of the quinolone antibiotic. The therapeutic implications of this interaction, if any, remain to be defined.