title: Preclinical pharmacokinetics, dose proportionality, gender difference and protein binding study of 16-dehydropregnenolone, an antihyperlipidemic agent, in rats.
abstract: OBJECTIVE
  This manuscript addresses key pharmacokinetic issues in support of the development of a potent candidate lipid-lowering drug molecule, 16-dehydropregnenolone (DHP).
  
  
  METHODS
  Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) assay for simultaneous estimation of DHP and its metabolites, including 5-pregnene-3β-ol-16, 17-epoxi-20-one (M(1) ) was validated in male and female Sprague-Dawley rat plasma and applied to different studies. Pharmacokinetic studies of DHP after intravenous and oral administration were carried out to assess any gender effect. Dose-proportionality after oral administration was assessed at three dose levels. Protein binding was estimated using the modified charcoal adsorption method.
  
  
  RESULTS
  Rapid elimination of DHP from the systemic circulation resulted in a comparatively lesser systemic exposure in male compare to female rats. The area under the curve (AUC) after oral administration in males was significantly different to females. The large volume of distribution and low degree of protein binding suggest extensive distribution of DHP. An increase in the oral dose led to a disproportionate change in peak concentration (C(max) ) and AUC, indicating variable absorption. However, the dose-normalized AUC and C(max) at two dose levels were not found to be statistically different.
  
  
  CONCLUSIONS
  The extent of conversion of DHP to M(1) was higher after oral administration in male rats but was insignificant in female rats. DHP showed low systemic oral bioavailability and exhibited dose-independent pharmacokinetics and gender differences.
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR, Lucknow, India.
authors.forename: Satyendra
authors.initials: S
authors.lastname: Suryawanshi
authors.lastname: Wahajuddin
authors.forename: Ram Chandra
authors.initials: RC
authors.lastname: Gupta
authors.forename: Shio Kumar
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011284:Pregnenolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D000960:Hypolipidemic Agents; C028109:16 alpha,17-epoxy-3 beta-hydroxy-5 alpha-pregnan-20-one; C003592:16-dehydropregnenolone; D011284:Pregnenolone; D011280:Pregnanolone