title: Pharmacokinetics of rifabutin.
abstract: We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.
authors.affiliation: Division of Clinical Pharmacology, Stanford University Medical Center, California 94305.
authors.forename: M H
authors.initials: MH
authors.lastname: Skinner
authors.forename: M
authors.initials: M
authors.lastname: Hsieh
authors.forename: J
authors.initials: J
authors.lastname: Torseth
authors.forename: D
authors.initials: D
authors.lastname: Pauloin
authors.forename: G
authors.initials: G
authors.lastname: Bhatia
authors.forename: S
authors.initials: S
authors.lastname: Harkonen
authors.forename: T C
authors.initials: TC
authors.lastname: Merigan
authors.forename: T F
authors.initials: TF
authors.lastname: Blaschke
mesh_terms: D000386:AIDS-Related Complex / Q000378:metabolism; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D017828:Rifabutin; D012294:Rifamycins / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000995:Antitubercular Agents; D012294:Rifamycins; D017828:Rifabutin