Pharmacokinetics and metabolism of mespirenone, a new aldosterone antagonist, in rat and cynomolgus monkey

Abstract

1. The pharmacokinetics and metabolism of mespirenone were examined in rat and cynomolgus monkey using the tritiated drug.

2. Following i.v. administration, mespirenone exhibited a short half-life and a high plasma clearance; after oral administration the unchanged compound was not detectable. Thus, mespirenone has to be considered a pro-drug.

3. From rat urine three metabolites were isolated by h.p.l.c. and identified by mass spectra and ¹H n.m.r., all having retained the 7α-sulphur substituent as a thiomethyl or a sulphinylmethyl group.

4. The 7α-thiomethyl metabolite had a half-life of six hours in rat plasma and its AUC value was 35% of that for total ³H.

5. As this metabolite has marked anti-aldosterone activity, it is an active metabolite that contributes to the pharmacological effect of mespirenone.