Metabolic Profiles of Minimally Absorbed Orlistat in Obese/Overweight Volunteers

Abstract

To determine the metabolic profile of minimally absorbed orlistat in obese/overweight patients, an open-label, single-dose study was performed in eight obese/overweight volunteers between 23 and 68 years of age. Each subject received a single oral dose of 360 mg orlistat containing approximately 400 muCi of 14C-labeled orlistat. Serial blood samples were collected at specified times over 10 hours after administration of orlistat for determination of total radioactivity, unchanged orlistat, and major metabolites in the plasma. Urine samples were collected over 24 hours and analyzed to evaluate the urinary recovery of total radioactivity and the profile of orlistat metabolites in the urine. In addition, all fecal samples were collected and analyzed for total radioactivity. Urinary and fecal recovery of the administered dose of total radioactivity were 1.13 +/- 0.50% (24-hour data only) and 96.4 +/- 18.1% (n = 7), respectively. Maximum observed concentration (Cmax) and time to Cmax (tmax) values of plasma total radioactivity were 150 +/- 51 ng.eq/mL and 6.8 +/- 1.5 hrs, respectively. All these parameters obtained in obese/ overweight subjects were similar to those reported previously in healthy subjects. On the basis of the area under the concentration-time curve from 0 to 10 hours (AUC0-10), two major metabolites comprise a total of approximately 42% of the total radioactivity in plasma. The primary metabolite (M1) has a short half-life (approximately 2 hours), whereas the secondary metabolite (M3) disappeared at a slower rate. No strikingly apparent difference in the urinary metabolic profile was observed between two gender groups. It is concluded that the disposition of orlistat appears to be similar between normal and obese/overweight subjects. Of the minimal fraction of the dose that was absorbed systemically, the presence of two major metabolites accounts for approximately 42%.

Changes in abdominal subcutaneous fat water content with rapid weight loss and long-term weight maintenance in abdominally obese men and women

“…Furthermore, orlistat is only minimally absorbed into the blood stream. 31 The noninvasive measurement of changes in water content of subcutaneous adipose tissue, although as yet not well characterised, may provide important insight on the metabolic changes that occur in subcutaneous fat tissue with weight loss and weight maintenance, and on the mechanisms that regulate those changes. The increased water content in abdominal subcutaneous fat tissue most probably indicates increased blood flow.…”

Current and Potential Drugs for Treatment of Obesity

“…Orlistat also did not affect a single dose of four different antihypertensive drugs, furosemide, captopril, nifedipine (816), or atenolol (819). Absorption of vitamins A and E and ␤-carotene may be slightly reduced (815,816), and this may require vitamin therapy in a small number of patients.…”

“…Because the drug partially inhibits triglyceride digestion, it is possible that nutrients or drugs might be less well absorbed (811). Because of its lipid solubility, less than 1% of an oral dose is absorbed and degraded into two major metabolites (815). Pharmacodynamic studies suggest that orlistat does not affect the pharmacokinetic properties of dioxin (816), phenytoin (816), warfarin (817), glyburide (817), oral contraceptives (818), or alcohol (808).…”

Orlistat limits cholesterol intestinal absorption by Niemann-pick C1-like 1 (NPC1L1) inhibition

“…In addition, orlistat is known to decrease dietary cholesterol absorption by inhibition of intestinal lipases (Mittendorfer et al, 2001). Orlistat's absorption and metabolism are minimal with 83% of the drug is primarily eliminated intact in the feces (Zhi et al, 1995;Zhi et al, 1996).…”