Orlistat reduces gallbladder emptying by inhibition of CCK release in response to a test meal.
OBJECTIVE
Orlistat is a covalent inhibitor of digestive lipase derived from lipstatin, the natural product of Streptomyces toxytricini. By blocking the active site of intestinal lipase, orlistat inhibits hydrolysis of dietary triglycerides and thus reduces the intestinal lipid absorption. It is uncertain whether intestinal inhibition of lipase by orlistat also interferes with nutrient-induced CCK release from intestinal I-cells. The aim of the present study was therefore to assess whether oral administration of orlistat inhibits CCK release in response to a test meal and thus causes impaired gallbladder emptying.


METHODS
22 healthy volunteers were given a test meal consisting of 200 ml dairy cream and two teaspoons of chocolate powder (552 kcal=2328 kJ; 56.0 g fat; 5.2 g proteins, 6.6 g carbohydrates), with and without oral application of 120 mg orlistat. Gallbladder volume was determined by ultrasound before and 5, 10, 20, 30 and 40 min after meal ingestion. In parallel, a venous blood sample was collected for the measurement of bioactive CCK. CCK activity was assessed using a bioassay with isolated rat pancreatic acini cells.


RESULTS
Oral administration of orlistat significantly impairs gallbladder emptying. After ingestion of the test meal the gallbladder contracted by 78.5% in the control group, whereas the test group with orlistat only showed a contraction of 45.7% (p<0.01). Maximal contraction was reached after 35 to 40 min, the maximal gallbladder emptying was delayed up to 10 min by orlistat. Orlistat induced a significant reduction of bioactive CCK levels in response to a test meal (CCK(max) with orlistat=4.1 pmol/l; CCK(max) without orlistat=7.8 pmol/l). CCK levels were reduced by 47% and the onset of maximal CCK secretion was delayed up to 10 min.


CONCLUSIONS
The inhibition of intestinal lipolytic activity by orlistat results in reduced gallbladder emptying through inhibition of meal-mediated CCK release. We therefore hypothesize that impaired gallbladder motility may represent a risk factor in chronic treatment of severe obesity using orlistat.
Ellrichmann
Mark
M
Department of Medicine I, St. Josef Hospital, Ruhr-University of Bochum, Gudrunstr. 56, 44791 Bochum, Germany. Mark.Ellrichmann@ruhr-uni-bochum.de <Mark.Ellrichmann@ruhr-uni-bochum.de>
Ritter
Peter R
PR
Otte
Jan-Michel
JM
Schrader
Henning
H
Banasch
Matthias
M
Brunke
Gabriele
G
Herzig
Karl-Heinz
KH
Seebeck
Jörg
J
Schmidt
Wolfgang E
WE
Schmitz
Frank
F
D000284:Administration, Oral; D000328:Adult; D002766:Cholecystokinin / Q000097:blood*; D018592:Cross-Over Studies; D004435:Eating / Q000502:physiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D016473:Gallbladder Emptying / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D016014:Linear Models; D008049:Lipase / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D000077403:Orlistat
D004791:Enzyme Inhibitors; D007783:Lactones; D002766:Cholecystokinin; D000077403:Orlistat; D008049:Lipase