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Dose‐dependent pharmacokinetics of KR‐31378, a new neuroprotective agent for ischaemia‐reperfusion damage in dogs
Author(s) -
Kim SunO.,
Kwak SangH.,
Lee Byung H.,
Lee DongH.,
Lim Hong,
Yoo SungE.,
Chung Hye J.,
Lee Myung G.
Publication year - 2004
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.391
Subject(s) - pharmacokinetics , beagle , oral administration , absorption (acoustics) , pharmacology , fissipedia , gastrointestinal tract , medicine , chemistry , anesthesia , physics , acoustics
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 µg 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 µg 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. Copyright © 2004 John Wiley & Sons, Ltd.