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Evidence of a drug–drug interaction linked to inhibition of ester hydrolysis by orlistat
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Bentley, Darren, Young, Annie M., Rowell, Lucy, Gross, Günter, Tardio, Joseph and Carlile, David (2012) Evidence of a drug–drug interaction linked to inhibition of ester hydrolysis by orlistat. Journal of Cardiovascular Pharmacology, 60 (4). pp. 390-396. doi:10.1097/FJC.0b013e31826731ff
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Official URL: http://dx.doi.org/10.1097/FJC.0b013e31826731ff
Abstract
Orlistat, a lipase inhibitor taken with meals at doses of 60 mg (available over-the-counter) or 120 mg (prescription only) for treatment of obesity, is known to impair the absorption of fat-soluble molecules. Dalcetrapib, a modulator of cholesteryl ester transfer protein activity, is a lipophilic thioester prodrug. Lipase-induced and pancreatin-induced hydrolysis of dalcetrapib in biorelevant media in vitro was very efficiently inhibited by orlistat. Thus, the potential for orlistat to affect the bioavailability of concomitantly administered dalcetrapib was studied in an open-label 2-cohort study in 24 healthy volunteers as follows: single 600-mg doses of dalcetrapib were administered with increasing doses of orlistat (cohort A: 10, 40, 120 mg; cohort B: 20, 60, 120 mg). Exposure to the active form of dalcetrapib was more than 50% lower when taken with orlistat 60 mg or 120 mg than when taken alone. Similar trends were observed with lower orlistat doses (20 mg and 40 mg). Concomitant administration of orlistat also reduced the pharmacodynamic effects of dalcetrapib treatment on cholesteryl ester transfer protein activity. The interaction exceeds that predicted on the basis of dalcetrapib lipophilicity. These findings demonstrate the potential for large interactions between orlistat and esters that undergo de-esterification in the gastrointestinal tract, independent of lipophilicity. Copyright © 2012 by Lippincott Williams & Wilkins.
| Item Type: | Journal Article | ||||
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| Subjects: | R Medicine > R Medicine (General) | ||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Health Sciences > Clinical Trials Unit Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Journal of Cardiovascular Pharmacology | ||||
| Publisher: | Wolters Kluwer Health | ||||
| ISSN: | 0160-2446 | ||||
| Official Date: | 1 October 2012 | ||||
| Dates: |
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| Volume: | 60 | ||||
| Number: | 4 | ||||
| Page Range: | pp. 390-396 | ||||
| DOI: | 10.1097/FJC.0b013e31826731ff | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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