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.

Isolation and identification of major metabolites of rifalazil in mouse and human

“…Rifalazil and its metabolites were analysed by hplc according to the method described previously (Hosoe et al 1994, 1996b, Mae et al 1996 with slight modi® cations. The isocratic mobile phase used in the present study was acetonitrile} citrate perchlorate buå er (1} 1 v} v) and the peaks were detected at 620 and} or 230 nm.…”

Prospects for development of new antimycobacterial drugs

“…61 In-vivo activity KRM has high tissue levels but low plasma levels in mice after oral administration, as is also the case with RBT, whereas RFP has high levels in both plasma and tissues. 116,130 AUCs were in the order KRM Ͼ RFP Ͼ RBT for lungs, KRM Ͼ RBT Լ RFP for spleen, RFP Ͼ KRM Ͼ RBT for liver, RFP Ͼ KRM Ͼ RBT for kidney, and RFP Ͼ KRM Լ RBT for plasma. Moreover, KRM had a longer time of elimination from tissues than did RFP and RBT, particularly in lungs and spleen, and exhibited non-linear kinetics of elimination.…”

Determination of rifalazil, a potent antibacterial agent, in human plasma by liquid–liquid extraction and LC–MS/MS

“…The pharmacokinetics of rifalazil were studied in rats and dogs, after intravenous and oral administration [7]. Rifalazil distributes readily to tissues, as reflected in a large volume of distribution in animals [7]. Given the low doses used in human clinical trials with a therapeutic dose at 25 mg, and a long terminal half-life at above 100 h observed in humans [5], it was important to develop a more sensitive assay in order to perform detailed pharmacokinetic studies.…”

“…Bioanalytical methodology for rifalazil has previously been described by Hosoe et al [6,7] for determination of rifalazil concentrations in plasma, whole blood, urine and tissue from rats and dogs. Solid phase extraction and liquid chromatography with UV detection was used for rat plasma with a lower limit of quantification (LLOQ) of 10 ng/mL.…”

“…Solid phase extraction and liquid chromatography with UV detection was used for rat plasma with a lower limit of quantification (LLOQ) of 10 ng/mL. The pharmacokinetics of rifalazil were studied in rats and dogs, after intravenous and oral administration [7]. Rifalazil distributes readily to tissues, as reflected in a large volume of distribution in animals [7].…”