Disposition and cardioselectivity of MDL 74,405, a vitamin E-like free radical scavenger, in rats and dogs after intravenous infusion
Kuo, B.S.; Mathews, B.S.; Stuhler, J.D.; Carrel, B.K.; Ho, J.; Rose, J.Q.
Drug Metabolism and Disposition the Biological Fate of Chemicals 23(7): 757-764
1995
ISSN/ISBN: 0090-9556 PMID: 7587965 Document Number: 441102
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. MDL 74,405, a quaternary ammonium ion, was rapidly and extensively distributed into most tissues in rats, but preferentially concentrated in the heart. For all tissues except spleen (1 hr), small intestine (1 hr), and large intestine (8 hr), peak concentrations occurred at 0.25 hr (or earlier) postdose. The drug distribution into erythrocytes was minimal, and transport across the blood-brain barrier was transient and minor. The heart/plasma concentration ratio was dramatically higher than for most other tissues for at least 24 hr. It increased to 261 at 3 hr, peaked at 276 at 5 hr, and gradually declined for the remainder of the study, with ratios of 250 at 8 hr and 120 at 24 hr. Except for eyes, erythrocytes, and bone marrow, the plasma area under the curve from 0 to infinity was the lowest and that of heart was the highest among all tissues ( apprx 200 times that of plasma). A (14C)HPLC chromatogram of heart tissue revealed that 95% of heart radioactivity was parent compound. These results document the cardioselectivity and sustained, high drug concentration in the rat heart. In view of pharmacokinetics, the rapid and preferential uptake of MDL 74,405 into the heart suggests it may be a promising drug candidate for the prevention of cardiac reperfusion injury associated with free radicals.