Disposition of the enantiomers of cromakalim in rat and cynomolgus monkey

Abstract

1. Disposition of the 3R,4S(+) and 3S,4R(-) enantiomers of the racemic antihypertensive drug cromakalim has been studied in rats and cynomolgus monkeys using the 14C-drug labelled in either the 3R,4S(+) or the 3S,4R(-) enantiomer. 2. After oral administration to rat, blood concentrations of the 3R,4S(+) enantiomer were up to fourfold higher than those of the 3S,4R(-) enantiomer. Metabolism of the former was not as extensive as that of the latter and consequently plasma and urinary radiometabolite patterns were quantitatively different. 3. In contrast to rat, there were much greater differences in the disposition of the two enantiomers following oral administration of cromakalim to the cynomolgus monkey. Plasma concentrations of the 3R,4S(+) enantiomer were approximately 100 x those of the 3S,4R(-) enantiomer and the rate of urinary 14C elimination for the 3R,4S(+) enantiomer was much faster than that for the 3S,4R(-) enantiomer. Plasma and urinary radiometabolite patterns were very different for the two isomers. Metabolic end products of the 3R,4S(+) enantiomer were predominantly phase I metabolites whereas the 3S,4R(-) enantiomer was almost entirely metabolized by glucuronidation. 4. A study of the racemic drug alone would have led to a misunderstanding of the fate of the compound in these species.