title: Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone.
abstract: OBJECTIVE
  To study the dose escalation pharmacokinetics and lipid lowering activity of a novel FXR modulator, 16-Dehydropregnenolone (DHP).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  DHP exhibits route and dose-dependent pharmacokinetics. Pharmacokinetic and lipid lowering activity by oral route indicate saturation of oral absorption at higher doses. The study contributes to the understanding of the plasma disposition pharmacokinetics of DHP and its metabolite in rats by oral and intravenous route of administration.
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR, Lucknow, Uttar Pradesh, India.
authors.forename: Devendra
authors.initials: D
authors.lastname: Kumar
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Khanna
authors.forename: Ram
authors.initials: R
authors.lastname: Pratap
authors.forename: Jitendra K
authors.initials: JK
authors.lastname: Sexana
authors.forename: Rabi S
authors.initials: RS
authors.lastname: Bhatta