Pharmacokinetics

Absorption

In normal weight and obese volunteers, the systemic exposure to Xenical (Orlistat) was minimal. Plasma concentrations of intact Orlistat were nearly non-measurable (< 5 ng/ml) following a single oral administration of 360 mg orlistat.

In general, after long-term treatment at therapeutic doses, detection of intact Orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/ml or 0.02 microM), without evidence of accumulation showing consistency with negligible absorption.

Distribution

The volume of distribution cannot be determined because Xenical (Orlistat) is minimally absorbed. In vitro Orlistat is > 99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Metabolism

Based on animal data, it is likely that the metabolism of Orlistat occurs mainly presystemically. Two major metabolites accounted for approximately 42% of the total radioactivity in plasma resulting from the minute fraction of the dose that was absorbed systemically in obese patients.

These two major metabolites have very weak lipase inhibitory activity (1000- and 2500-fold less than Orlistat respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 ng/ml and 108 ng/ml respectively), these metabolites are pharmacologically inconsequential.

Elimination

Studies in normal weight and obese subjects have shown that fecal excretion of the unabsorbed Xenical (Orlistat) was the major route of elimination. Approximately 97% of the administered dose was excreted in faeces and 83% of that as unchanged Orlistat.

The cumulative renal excretion of total Orlistat-related materials was < 2% of the given dose. The time to reach complete excretion (fecal plus urinary) was 3-5 days. The disposition of Orlistat appeared to be similar between normal weight and obese volunteers.