Effects of pretreatment with SKF-525A on triphenyltin metabolism and toxicity in mice.

The effects of cytochrome P-450 inhibition by alpha-phenyl-alpha-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), which inhibits the activity of a number of cytochrome P-450s, on triphenyltin metabolism and toxicity in mice were studied. At 24 h after triphenyltin administration, the triphenyltin levels in the tissues of SKF-525A-pretreated mice were about three times of those in the tissues of SKF-525A-untreated mice and the ratio of metabolites to parent triphenyltin in the tissues of SKF-525A-pretreated mice was lower than those in the tissues of SKF-525A-untreated mice. These data indicate that the pretreatment of SKF-525A decelerated the triphenyltin metabolism and increased triphenyltin accumulation in the tissues of mice. Although triphenyltin did not affect plasma glucose levels of in the SKF-525A-untreated mice, the triphenyltin produced marked hyperglycemia in SKF-525A-pretreated mice. These results suggest that the inhibition of cytochrome P-450 system enzymes by SKF-525A affects the metabolism and toxicity of triphenyltin and has a key role in inducing the hyperglycemic action of triphenyltin, i.e. by increasing triphenyltin accumulation in the mice.