Review of Limited Systemic Absorption of Orlistat, a Lipase Inhibitor, in Healthy Human Volunteers

Zhi, Jianguo; Melia, Angela T.; Eggers, Herwig; Joly, Raymond; Patel, Indravadan H.

doi:10.1002/j.1552-4604.1995.tb04034.x

Cited by 158 publications

(92 citation statements)

References 8 publications

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“…In oral application as anti-obesity treatment, orlistat shows little side effects. Overdosage in humans with increased systemic uptake did not reveal severe side effects 43 and animal models with extreme overdosage did not reveal cytotoxic effects of orlistat either (FDA hearing protocol).…”

Section: Discussionmentioning

confidence: 99%

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

et al. 2007

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Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5 þ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5 þ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n ¼ 26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a halfmaximal dose (IC 50 ) of 2.35 lM. In healthy B cells a significantly higher mean IC 50 of 148.5 lM of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; Po0.001). Orlistat-mediated cytotoxicity was decreased by BCR stimulation. Finally, the cytotoxic effects of orlistat on primary CLL cells were enhanced by the simultaneous incubation with fludarabine (P ¼ 0.003). In summary, alterations of lipid metabolism are involved in CLL pathogenesis and might represent a novel therapeutic target in CLL.

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Section: Discussionmentioning

confidence: 99%

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

et al. 2007

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“…The successful introduction of Orlistat to the market has demonstrated that drugs that inhibit the absorption of dietary fat can be efficacious for obesity treatment (13,14). However, the mechanism for Orlistat, which is to inhibit pancreatic lipase, leads to the undesirable side effect of fecal leakage (15).…”

Section: Discussionmentioning

confidence: 99%

Identification of Acyl Coenzyme A:Monoacylglycerol Acyltransferase 3, an Intestinal Specific Enzyme Implicated in Dietary Fat Absorption

Cheng

Nelson

Chen

et al. 2003

Journal of Biological Chemistry

139

102

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Acyl coenzyme A:monoacylglycerol acyltransferase (MGAT) catalyzes the synthesis of diacylglycerol using 2-monoacylglycerol and fatty acyl coenzyme A. This enzymatic reaction is believed to be an essential and ratelimiting step for the absorption of fat in the small intestine. Although the first MGAT-encoding cDNA, designated MGAT1, has been recently isolated, it is not expressed in the small intestine and hence cannot account for the high intestinal MGAT enzyme activity that is important for the physiology of fat absorption. In the current study, we report the identification of a novel MGAT, designated MGAT3, and present evidence that it fulfills the criteria to be the elusive intestinal MGAT. MGAT3 encodes a ϳ36-kDa transmembrane protein that is highly homologous to MGAT1 and -2. In humans, expression of MGAT3 is restricted to gastrointestinal tract with the highest level found in the ileum. At the cellular level, recombinant MGAT3 is localized to the endoplasmic reticulum. Recombinant MGAT3 enzyme activity produced in insect Sf9 cells selectively acylates 2-monoacylglycerol with higher efficiency than other stereoisomers. The molecular identification of MGAT3 will facilitate the evaluation of using intestinal MGAT as a potential point of intervention for antiobesity therapies.

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“…Detectable orlistat plasma levels (0.2 ± 3.37 ngaml) were most frequently found 2 ± 6 h after the morning dose on day 5. The detected levels of drug did not exceed those observed in the plasma monitoring program 12 at the same 120 mg dosage level (`5 ngaml).…”

Section: Pharmacokineticsmentioning

confidence: 61%

“…11 Results of Phase 1 plasma monitoring studies 12 con®rmed that the systemic exposure of orlistat is extremely low and no pharmacokinetics can be de®ned. On the other hand, for a locally acting therapeutic product, a potential risk exists if the active substance is absorbed.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Orlistat fails to alter postprandial plasma lipid excursions or plasma lipases in normal-weight male volunteers

Shepard

Jensen

Blotner³

et al. 2000

Int J Obes

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OBJECTIVES: After 10 d of orlistat administration (120 mg three timesaday), the primary objective was to determine the drug's effect on postprandial plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities on day 10 after an oral fat-load. The secondary objectives were to determine the effects of orlistat on 12 h postprandial measures of: (1) preheparin HTGL and LPL; and (2) serum triglycerides, very-low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol and free fatty acids. METHODS: Twenty-four normal-weight, healthy male volunteers were randomized to either 120 mg orlistat (n 12) or placebo (n 12) three times a day with meals for 10 d. Preheparin LPL and HTGL activities and LPL speci®c activity were measured in the fasted state on days 1, 5, and 10. On days 5 and 10 the study medication (orlistat or placebo) was taken at the beginning of a fat-rich breakfast and serum lipid and lipoprotein levels monitored for 12 h postprandially. On day 10, 15 min postheparin HTGL activity was measured 8 h after the fat-rich breakfast. RESULTS: No differences were found between groups in fasting levels of preheparin LPL or HTGL activity or in LPLspeci®c activity on days 1, 5 and 10. No difference was found between the two treatment groups in postheparin HTGL activity 8 h after the fat-rich breakfast. Also, no differences were found between the two groups in plasma triglycerides or lipoproteins. CONCLUSION: The results indicate that the oral administration of orlistat (120 mg t.i.d.) does not signi®cantly alter plasma triglycerides or lipoproteins, and that the inhibitory effect of orlistat on lipases is limited to the gastrointestinal tract and is not manifested systemically.

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Review of Limited Systemic Absorption of Orlistat, a Lipase Inhibitor, in Healthy Human Volunteers

Cited by 158 publications

References 8 publications

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

Identification of Acyl Coenzyme A:Monoacylglycerol Acyltransferase 3, an Intestinal Specific Enzyme Implicated in Dietary Fat Absorption

Orlistat fails to alter postprandial plasma lipid excursions or plasma lipases in normal-weight male volunteers

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