The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volunteers who received a single, oral dose of rifapentine (600 mg). Subgroups of five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL) at timed intervals following drug administration. Drug concentrations, including the concentration of the primary metabolite 25-desacetyl rifapentine, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pressure liquid chromatography. The concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The concentration-time data were fit to two-compartment (plasma) or one-compartment (AC and ELF) models. The peak concentrations in plasma, ELF, and AC, 26.2, 3. 7, and 5.3 microg/ml, respectively, occurred at 5, 5, and 7 h after drug administration, respectively. The half-lives and areas under the curve for plasma, ELF, and AC were 18.3 h and 520 microg. h/ml, 20.8 h and 111 microg. h/ml, and 13.0 h and 133 microg. h/ml, respectively. Although the intrapulmonary rifapentine concentrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis (0.5 microg/ml) for the 48-h observation period. These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.