Orlistat Anti-obesity Agent, Gastric and Pancreatic Lipase Inhibitor

Synonyms. Orlipastat; Ro±18±0647; Ro±18±0647/002; (í)-Tetrahydrolipstatin. Proprietary name. Xenical N-Formyl-l-leucine (1S)-1-[[(2S,3S)-3±hexyl±4±oxo±2±oxetanyl]-methyl]dodecyl ester C29H53NO5=495.7 CAS²96829±58±2

A white to off±white crystalline powder. M.p 40° to 43°. It is practically insoluble in water; freely soluble in chloroform; very soluble in methanol and ethanol.

Dissociation constant.
pKa out of physiological range.

High Performance Liquid Chromatography.
Column: Spherisorb C6 (100 × 2 mm, 2 m). Mobile phase: (A) acetonitrile:0.1% formic acid (95:5), flow rate 150 L/min; (B) methanol:water (85:15), flow rate 150 L/min. Rapid change to 100% methanol at 300 L/min for 3 min then re±equilibration with 85% methanol. MS±MS detection. Retention time: (A) 1.1 min; (B) 2.4 min. [R. Wieboldt et al.,J. Chromatogr. Biomed. Sci. Appl.,1998, 708, 121±129].

Quantification.

High performance liquid chromatography±mass spectrometry. In plasma: limit of quantification 0.3 g/L, MS±MS detection²R. Wieboldt et al.,J. Chromatogr. Biomed. Sci. Appl.,1998, 708, 121±129. In plasma: limit of detection 0.2 g/L, MS±MS detection²P. K. Bennett et al.,J. Mass Spectrom.,1997, 32, 739±749. In serum: limit of detection 0.25 g/L²X. Xu et al.,J. Mass Spectrom.,2000, 35, 1329±1334.

Disposition in the Body.
Orlistat is not absorbed following oral administration and plasma concentrations of intact orlistat are non±measurable. There is no evidence of accumulation and no defined systemic pharmacokinetics. Metabolism may occur within the gastro±intestinal wall. There are two metabolites M1 (4±member lactone ring hydrolysed) and M3 (M1 with N-formyl leucine moiety cleaved) which account for approximately, 42% of the total plasma concentration. Elimination is mainly by faecal excretion of the unabsorbed drug with approximately, 97% of the administered dose excreted in this way, 83% of which is the unchanged drug. Cumulative renal excretion of total orlistat related material was <2% of the dose. Complete excretion occurs within 3 to 5 days. Orlistat, M1 and M3 are all subject to biliary excretion. Therapeutic concentration. With therapeutic doses, detection of intact orlistat in plasma is difficult and concentrations are extremely low, <10 g/L. Low plasma levels of M1 (26 g/L) and M3 (108 g/L) are observed 2 to 4 h after a therapeutic dose. <5 g/L 8 h following administration with 360 mg orlistat. Half±life. Ranges between 1 and 2 h for the parent drug; for the metabolites approx. 2 h for M1 and 13.5 h for M3. Volume of distribution. Cannot be determined since minimally absorbed and no definite systemic pharmacokinetics. Distribution in blood. Minimally partitions into erythrocytes. Protein binding. >99%. Mainly lipoprotein and albumin.

Dose.
120 mg three times a day.

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