Abstract
Hydroxyprogesterone caproate (17-OHPC) is used to prevent preterm labor in pregnant subjects. In the present study inter-species difference in the metabolism of 17-OHPC was evaluated using liver microsomes from mouse, rat, rabbit, pig, dog and baboon and compared with human liver microsomes and primary human hepatocyte cultures. In all the species evaluated, monohydroxylated 17-OHPC was observed to be the major metabolite. Significant inter-species difference in the rate of 17-OHPC metabolism was observed both qualitatively and quantitatively. Ketoconazole inhibited 17-OHPC metabolism in all the species evaluated confirming the dominant role of CYP3A (rats, rabbits, dog, pig, dog, baboon) and cyp3a (mice) in the metabolic pathway. It is concluded that monohydroxylated 17-OHPC is the major metabolite of 17-OHPC in various animal species. The baboon seems to provide the most suitable model for evaluating the pharmacokinetics of 17-OHPC in animals and screening for potential drug-drug interactions although interspecies variation exists in the disposition of 17-OHPC.
Highlights
Hydroxyprogesterone caproate (17-Hydroxypregn-4-ene-3-20Dione, 17-OHPC), a synthetic hormone produced by the esterification with caproic acid at the 17 carbon position of the metabolite of the natural female sex hormone progesterone, is an agent used in the prevention of preterm delivery
We have previously shown that 17-OHPC is metabolized by CYP3A4 and CYP3A5 in humans leading to the generation of a monohydroxylated 17-OHPC (m/z=445.0) as the major metabolite
Metabolic profiles generated by incubation of 17-OHPC with microsomes derived from various species (Mouse, Rat, Rabbit, Pig, Dog and Baboon) were compared with human liver microsomes and primary human hepatocytes
Summary
Hydroxyprogesterone caproate (17-Hydroxypregn-4-ene-3-20Dione, 17-OHPC), a synthetic hormone produced by the esterification with caproic acid at the 17 carbon position of the metabolite of the natural female sex hormone progesterone, is an agent used in the prevention of preterm delivery. It is a lipophillic molecule having a molecular weight of 428.7, a log p value of 4 with no apparent charges on the molecule. The objectives of the study presented here are 1) to investigate and compare the formation and kinetics of 17-OHPC hydroxymetabolite in mouse, rat, rabbit, beagle dog, guinea pig and baboon liver microsomes, 2) to search for a suitable animal model for further study of 17-OHPC metabolism and pharmacokinetics and potential. The kinetics of 17-OHPC metabolism in humans will be evaluated in detail using expressed human CYP3A isoforms
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