Inhibition of gastrointestinal lipolysis by Orlistat during digestion of test meals in healthy volunteers

The inhibition of digestive lipases by the antiobesity drug Orlistat along with lipolysis levels and fecal fat excretion were measured in healthy huma ns. Orlistat was found to be a powerful gastric lipase inhibitor, achieving 46.6-91.4% enzyme inhibition and thus greatly reducing gastric lipolysis o f solid and liquid meals (11-33% of respective controls). Gastric lipase in hibition by Orlistat was extremely fast (half-inhibition time, <1 min). Duo denal lipolysis was reduced significantly by Orlistat given with the solid meal (32.6-37.6% of controls) but was only slightly reduced by Orlistat giv en with the liquid meal (74.5-100% of controls). Human pancreatic lipase (H PL) inhibition was found to be high (51.2-82.6%), however, regardless of th e meal. These paradoxical results were explained when in vitro lipolysis ex periments were performed. The rates of HPL inhibition by Orlistat were foun d to be similar with both types of meals (half-inhibition time 5-6 min), bu t the preemulsified triglycerides of the liquid meal were rapidly hydrolyze d by HPL before the enzyme was significantly inhibited by Orlistat. With th e solid meal, the rate of hydrolysis of the meal triglycerides by HPL was s lower than the rate of HPL inhibition by Orlistat. As predicted from the pr evious results, the effects of Orlistat on fat excretion levels were found to be much greater with the solid (40.5-57.4% of ingested fat) than with th e liquid (4.2-18.8%) test meal.