The Effects of Somatostatin and Selected Analogs on Lipid Absorption in Animals
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Based upon the clinical finding that a Merck somatostatin-14 (S-14) analog (1) induced steatorrhea in man, we sought to develop animal models to study the effects of S-14 and a series of synthetic analogs on absorption.
Rats were trained to eat a diet (preweighed) containing 15% fat. Following the feeding period, the remaining diet was removed and the amount consumed recorded. This food conditioning of the rats was continued until the rats consumed approximately 15 g of the diet per day. Feces were collected and weighed prior to feeding periods. On test days, S-14 or analogs were administered sc to rats immediately prior to feeding. For each compound tested, fat absorption decreased in dose-dependent fashion. For example, S-14 at 0.5 mg/kg did not increase % of dietary fat in feces (% DFF). At 1.0 mg/kg, S-14 increased % DFF from 7.9 to 10.2 (p <0.01, pretest day vs test day), and at 10 mg/kg S-14, % DFF increased from 9.1 to 12.8 (p <0.001).
For each analog, the subcutaneous dose required to decrease fat absorption in rats was several orders of magnitude higher than the intravenous dose required to inhibit insulin and glucagon. Moreover, the threshold for production of statistically significant increases in fecal fat differed among analogs when compared to their endocrine potencies. One analog administered in the model for 14 days was shown to produce consistent fat malabsorption throughout the entire test period; however, this lipid malabsorption was substantially more pronounced on the first three days of the treatment period. When the compound was not administered on day 15, the % DFF significantly decreased.
In an attempt to develop a system more suitable for rapid screening, pancreatic secretagogues such as secretin or cholecystokinin, were administered intravenously to anesthetized rats whose duodena had been cannulated and perfused to enable collection of pancreatic secretions. Total amylase, lipase, and protein were determined in single animals in response to a secretagogue, both before and after iv pretreatment by S-14 or an analog. Pancreatic enzyme secretion in response to sequential secretagogue-stimulation was found to be reproducible for up to three injections and behaved in a dose-dependent fashion. In general, secretagogue-induced increases in amylase, lipase, and total protein were comparable.
Pretreatment with the S-14 analogs substantially inhibited secretagogue-induced pancreatic exocrine secretion and was dose-dependent. Individual potencies correlated well with the ability to inhibit endocrine hormone release (glucagon, insulin, and growth hormone), although one compound with significantly less exocrine inhibitory effect was noted.
Our experience demonstrates that it is possible to produce S-14-induced fat malabsorption in rats, when fed a lipid rich diet. The animal models described herein show that S-14 and selected S-14 analogs have different potencies to induce fat malabsorption in rat and to inhibit exogenously stimulated pancreatic enzyme release. Nonetheless, the potential clinical significance of these separations is difficult to predict.
KeywordsShort Bowel Syndrome Gastric Inhibitory Polypeptide Pancreatic Enzyme Secretion Food Conditioning Lipid Malabsorption
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