title: Dose-dependent pharmacokinetics of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage in dogs.
abstract: Dose-dependent pharmacokinetic parameters of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage, were evaluated after intravenous and oral administration of the drug at doses of 5, 10 and 25 mg/kg to male beagle dogs. After intravenous administration, the dose-normalized (based on 5 mg/kg) areas under the plasma concentration-time curve from time zero to time infinity (AUC values, 725, 1450 and 2300 micro g min/ml for 5, 10 and 25 mg/kg, respectively) were significantly different among the three dose ranges studied; the value increased more proportionally as the dose increased. This could be due to slower total body clearance (Cl) with increasing doses (6.90, 3.46 and 2.17 ml/min/kg). The slower Cl value with increasing doses may be due to saturable metabolism of KR-31378 in dogs. After oral administration, the dose-normalized (based on 5 mg/kg) AUC values (833, 1450 and 1920 micro g min/ml) at 5 mg/kg were significantly smaller than those at 10 and 25 mg/kg. Note that the AUC values were comparable (not significantly different) between intravenous and oral administration at all doses studied, indicating that the absorption of KR-31378 from the gastrointestinal tract was essentially complete and the first-pass (gastric, intestinal and/or hepatic first-pass) effects were almost negligible in dogs.
authors.affiliation: AgroPharma Research Institute, Dongbu Hannong Chemical Company, 103-2 Moonji-Dong, Daeduck Science Town, Taejeon 305-708, Republic of Korea. sokim_99@msn.com
authors.forename: Sun-O
authors.initials: SO
authors.lastname: Kim
authors.forename: Sang-H
authors.initials: SH
authors.lastname: Kwak
authors.forename: Byung H
authors.initials: BH
authors.lastname: Lee
authors.forename: Dong-H
authors.initials: DH
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Lim
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Yoo
authors.forename: Hye J
authors.initials: HJ
authors.lastname: Chung
authors.forename: Myung G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D001682:Biological Availability; D002545:Brain Ischemia / Q000150:complications; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011714:Pyrans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000209:etiology; D013997:Time Factors
chemical_list: D006146:Guanidines; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D018696:Neuroprotective Agents; D011714:Pyrans