薬物代謝と毒性学ジャーナル
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概要

Pharmacokinetics, Metabolism and Excretion of Hypolipidemic DRUG: 16-Dehydropregnenolone

Pratima Srivastava, Neha Mathur and Ashim Ghatak

Purpose: 16-dehydropregnenolone/DHP/CDRI-80/574, a new orally effective hypolipidemic agent presently in advanced clinical trials. This paper aims to study the absorption, distribution, metabolism and excretion profiles in order to delineate the possible cause(s) behind low bioavailability of CDRI-80/574 and also strategy to enhance the same. "
Methods: Metabolic, Excretion and Pharmacokinetics studies were conducted in the Sprague-Dawley rats.
Results: CDRI-80/574 exhibited log D: 4.5, absorption-half-life of 18 min and -constant 0.04/min by closed loop intestinal model in rats, was stable in gastric juice and 30% of RBCs transport/uptake was noted. CDRI-80/574 undergoes rapid metabolism in rat hepatic microsomal fractions; however extra hepatic tissues (intestinal-wall and -microvilli), showed less metabolism. IC50 of CDRI-80/574 was 2.22 nM, Km =15.8 nM, Vmax= 0.46 nmoles/mg protein/min, t1/2 was 3 min in microsomes. CDRI-80/574 was comparatively more stable in human hepatocytes (t1/2= 8.7 min) than rats (t1/2= 4.6 min). Aminobenzotriazole, ketoconazole, diltiazem and grapefruit juice inhibited CDRI- 80/574 metabolism, whereas, its metabolism was induced by phenobarbitone. Epoxy metabolite of CDRI-80/574 was synthesized and characterized. About 15% of CDRI-80/574 and 4 metabolites (hydrolysis/hydroxylation; m/z 317/319/321/330) were detected in feces. CDRI–80/574 was 7% bioavailable and exposure increased (2 fold) by grapefruit juice. Human CLinvivo was predicted to be 2.7 L/h/kg (45.83 ml/min/kg) by allometric scaling.
Conclusion: CDRI-80/574 is the first hypolipidemic, synthetic compound of pregnane series, hence it is important to elucidate the major reason for its low bioavailability. The compound was fast metabolized by CYP3A4. Further the inhibitors of CYP3A4 were able to increase the bioavailability of CDRI-80/574.