Orlistat

Anti-obesity Agent, Gastric and Pancreatic

Lipase Inhibitor
Synonyms. Orlipastat; Ro–18–0647; Ro–18–0647/002; (−)-Tetrahydrolipstatin.

Proprietary name. Xenical

N-Formyl-l-leucine (1S)-1-[[(2S,3S)-3–hexyl–4–oxo–2–oxetanyl]-methyl]dodecyl ester

C29H53NO5=495.7

CAS—96829–58–2

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 μm). Mobile phase: (A) acetonitrile:0.1% formic acid
(95:5), flow rate 150 μL/min; (B) methanol:water (85:15), flow rate 150 μL/min. Rapid change
to 100% methanol at 300 μL/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 μg/L, MS–MS detection—R. Wieboldt et al.,J.

Chromatogr. Biomed. Sci. Appl.,1998, 708, 121–129. In plasma: limit of detection 0.2 μg/L,
MS–MS detection—P. K. Bennett et al.,J. Mass Spectrom.,1997, 32, 739–749. In serum: limit of
detection 0.25 μg/L—X. 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 μg/L. Low plasma levels of M1 (26 μg/L) and M3 (108 μg/L) are observed 2
to 4 h after a therapeutic dose. <5 μg/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.