title: Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs.
abstract: The pharmacokinetics of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin (KRM-1648) in rats and dogs given a single oral dose of 3, 30, or 100 mg/kg of body weight were studied. In the rats, the concentrations of KRM-1648 in plasma, whole blood, and tissues peaked between 2.0 and 24.0 h, with elimination half-lives ranging from 6.2 to 19.5 h. The peak concentrations and the areas under the concentration-versus-time curves (AUC) for whole blood and tissues were 2 to 277 times higher than those for plasma. The high levels of KRM-1648 in tissues were consistent with its large volume of distribution (in excess of 10 liters/kg). A nonlinear increase in peak concentrations and AUCs for plasma, whole blood, and tissues occurred as the dose was increased and was consistent with the dose-dependent decrease in bioavailability. In the dogs, KRM-1648 levels in plasma and whole blood also exhibited a late time to the peak concentration (ranging from 4.0 to 11.2 h), a long elimination half-life (ranging from 15.2 to 24.0 h), and nonlinear kinetics. KRM-1648 exhibited high levels of plasma protein binding (more than 99%) and a high degree of affinity for lipoproteins in the plasma of both animals. After administration of KRM-1648, measurable levels of its metabolites, 25-deacetyl KRM-1648 in rats and 25-deacetyl KRM-1648 and 30-hydroxy KRM-1648 in dogs, were found in the biological samples tested. Thus, KRM-1648 is characterized by a high tissue affinity, a long elimination half-life, and nonlinear pharmacokinetics.
authors.affiliation: Takasago Research Laboratory, Hyogo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hosoe
authors.forename: T
authors.initials: T
authors.lastname: Mae
authors.forename: E
authors.initials: E
authors.lastname: Konishi
authors.forename: K
authors.initials: K
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: T
authors.initials: T
authors.lastname: Yamane
authors.forename: T
authors.initials: T
authors.lastname: Hidaka
authors.forename: T
authors.initials: T
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012294:Rifamycins / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000904:Antibiotics, Antitubercular; D008074:Lipoproteins; D012294:Rifamycins; C068980:KRM 1648