Disposition and cardioselectivity of MDL 74,405, a vitamin E-like free radical scavenger, in rats and dogs after intravenous infusion.
The disposition kinetics of MDL 74,405, a potent free radical scavenger for cardiac reperfusion and a vitamin E analog, was investigated in rats (1.2, 6.0, and 12 mg/kg) and dogs (1 and 10 mg/kg) after an intravenous infusion. Because the heart is the target site of drug action, a tissue distribution study was also conducted in rats (1.2 mg/kg) to explore the affinity of the drug to rat heart. In both animal species, plasma drug concentrations declined rapidly in the early distribution phase and exhibited a multiexponential pattern of elimination. Of the total excretion (95-96% of the dose) in 120 hr in rats, 45-51% was excreted in urine and 45-50% in feces. Of the total excretion (86-89% of the dose) in 120 hr in dogs, 41-43% of the dose was excreted in urine and 41-43% in feces. The dose was excreted mainly unchanged (62-78% in rat and 80-86% of the dose in dog urine) with several potential minor metabolites, indicating that renal and biliary excretions are the two major, equally important, routes of drug elimination in both species. Rats cleared the drug from the body markedly faster than dogs: the mean residence time in rats. (1.9-3.2 hr) was 15-20 times shorter, the terminal elimination half-life in rats (3.6-7.0 hr) was 10 times shorter; and the total clearance in rats (148-216 ml/min/kg) was 6-9 times greater. The steady-state volume of distribution was very large for both species. (19-37 liters/kg for rats and 59-64 liters/kg for dogs), which is consistent with the extensive tissue uptake of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Kuo
B S
BS
Preclinical Pharmacokinetics, Marion Merrell Dow, Inc., Ann Arbor, MI, USA.
Mathews
B S
BS
Stuhler
J D
JD
Carrel
B K
BK
Ho
J
J
Rose
J Q
JQ
D000818:Animals; D002250:Carbon Radioisotopes; D002317:Cardiovascular Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D016166:Free Radical Scavengers / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
D002250:Carbon Radioisotopes; D002317:Cardiovascular Agents; D016166:Free Radical Scavengers; C067190:MDL 73404; D014810:Vitamin E