title: Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics.
abstract: Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50 mg/kg for oral administration), rats (5, 10 and 20 mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (V(ss)) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were ClxMLP=49.8 W(0.861), Cl=5.20 W(0.523) and V(ss)=4.46 W(0.764). Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Soo K
authors.initials: SK
authors.lastname: Bae
authors.forename: Shin J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Yoon G
authors.initials: YG
authors.lastname: Kim
authors.forename: So H
authors.initials: SH
authors.lastname: Kim
authors.forename: Jin W
authors.initials: JW
authors.lastname: Kim
authors.forename: Taekrho
authors.initials: T
authors.lastname: Kim
authors.forename: Myung G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D011237:Predictive Value of Tests; D011719:Pyrazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013871:Thiones; D013876:Thiophenes; D014018:Tissue Distribution
chemical_list: D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz