Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone.

Indian Journal of Pharmacology
Devendra KumarR S Bhatta

Abstract

To study the dose escalation pharmacokinetics and lipid lowering activity of a novel FXR modulator, 16-Dehydropregnenolone (DHP). The disposition of DHP following oral (36, 72, 100 and 150 mg/kg) and intravenous (1, 5 and 10 mg/kg) administration and its dose-response relationship were carried out in Sprague-Dawley rats. DHP and its metabolite 5-pregnene-3β-ol-16, 17-epoxy-20-one (M1) were analyzed by a validated LC-MS/MS method in plasma after intravenous and oral administration. Dose escalation lipid lowering activities were carried out by triton-induced hyperlipidemic model. Oral administration resulted in higher amount of M1 formation as compared to intravenous administration. Dose escalation intravenous administration (1, 5 and 10 mg/kg) resulted in nonlinear increase in AUC of DHP. This was due to saturation of metabolism. On the contrary, systemic AUC and C(max) after oral administration show non-linear pharmacokinetics where saturated systemic DHP and M1 pharmacokinetics was observed above 72 mg/kg, indicating saturated oral absorption. Lipid lowering activity by its oral route of administration was in accordance with its pharmacokinetic profile and reached saturation above 72 mg/kg. DHP exhibits route and dose-dependen...Continue Reading

References

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Citations

Jul 2, 2015·Future Medicinal Chemistry·Valentina SepeAngela Zampella
May 26, 2016·The Journal of Steroid Biochemistry and Molecular Biology·Rachumallu RamakrishnaRabi Sankar Bhatta
Mar 19, 2016·Drug Metabolism Reviews·Mohd Yaseen MalikJawahar Lal

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