Metabolism and pharmacokinetics of progesterone in the cynomolgus monkey (Macaca fascicularis)

[4 -¹⁴C]Progesterone was administered to two cycling female monkeys during the luteal phase of the cycle, and blood and urine were sampled over a 24 h period. Progesterone had a volume of distribution of 1.75 ± 0.3 L/kg, and a plasma elimination clearance of 0.06 ± 0.03 L/kg/min. In comparison to the human, plasma progesterone binding was greater and progesterone clearance was slower in the cynomolgus monkey. The major unconjugated metabolite in plasma was 20α-hydroxy-4-pregnen-3-one. In urine 6.2% of ¹⁴C - steroids were unconjugated, 2.3% of which were [¹⁴C]progesterone. Thin-layer chromatography (TLC) of conjugated metabolites in urine revealed that 24% had the mobility of sulfates, 19% that of glucuronides, and 52% were more polar. After hydrolysis of conjugates, a major fraction chromatographed with pregnanediol. However, despite evidence for the presence of a 20α-hydroxyl group, none of the pregnanediol isomers could be identified among these ¹⁴C - steroids. Nevertheless, over 80% of urinary metabolites had sufficient analogy to pregnanediol to bind to an antiserum specific for ring D and the C-17 side-chain of pregnanediol.