METABOLIC PROFILES OF MINIMALLY ABSORBED ORLISTAT IN OBESE OVERWEIGHTVOLUNTEERS/

To determine the metabolic profile of minimally absorbed orlistat in o bese/overweight patients, an open-label, single-dose study was perform ed in eight obese/overweight volunteers between 23 and 68 years of age . Each subject received a single oral dose of 360 mg orlistat containi ng approximately 400 mu Ci of C-14-labeled orlistat. Serial blood samp les were collected at specified times over 10 hours after administrati on of orlistat for determination of total radioactivity, unchanged orl istat, and major metabolites in the plasma. Urine samples were collect ed over 24 hours and analyzed to evaluate the urinary recovery of tota l radioactivity and the profile of orlistat metabolites in the urine. In addition, all fecal samples were collected and analyzed for total r adioactivity. Urinary and fecal recovery of the administered dose of t otal radioactivity were 1.13 +/- 0.50% (24-hour data only) and 96.4 +/ - 18.1% (n = 7), respectively. Maxim um observed concentration (C-max) and time to C-max (t(max)) values of plasma total radioactivity were 150 +/- 51 ng . eq/mL and 6.8 +/- 1.5 hrs, respectively. All these par ameters obtained in obese/ overweight subjects were similar to those r eported previously in healthy subjects. On the basis of the area under the concentration-time curve from 0 to 10 hours (AUC(0-10)), two majo r metabolites comprise a total of similar to 42% of the total radioact ivity in plasma. The primary metabolite (M1) has a short half-life (si milar to 2 hours), whereas the secondary metabolite (M3) disappeared a t a slower rate. No strikingly apparent difference in the urinary meta bolic profile was observed between two gender groups. II is concluded that the disposition of orlistat appears to be similar between normal and obese/overweight subjects. Of the minimal fraction of the dose tha t was absorbed systemically, the presence of two major metabolites acc ounts for similar to 42%.