Abstract
Inhibitory effects of a newly developed benzodiazepine derivative (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1-jk][1,4] benzodiazepine-3yl]-1H-indole-2-carboxamide (FK480), a cholecystokinin (CCK) -A receptor antagonist, on pancreatic exocrine secretion were examinedin vivo in anesthetized rats. The antagonism produced by FK480 was competitive in nature because intraduodenal as well as intravenous infusion of FK480 (50–250 nmol/kg/hr) caused a parallel rightward shift of the entire dose-response curve for cerulein-stimulated pancreatic exocrine secretion without altering the maximal increase. The magnitude of the shift was proportional to the dose of FK480. The mean pA2 and ID50 values of intravenously administered FK480 were 8.2 and 24 nmol/kg/hr, respectively, and those of intraduodenally infused FK480 were 7.7 and 168 nmol/kg/hr, respectively. Thus, FK480 given by the intravenous route was about sevenfold more potent than that given by the oral route. The antagonistic effects produced by intravenous FK480 were specific for CCK receptor in that the stimulatory effects of cerulein were inhibited whereas those of bombesin and secretin were not altered. In addition, intravenous administration of 50 nmol/kg/hr FK480 completely suppressed pancreatic exocrine secretion in response to intraduodenal infusion of 10% casein (400 mg/hr). FK480 was active as a CCK receptor antagonist for more than 12 hr because oral administration of FK480 (1.0 mg/kg) had significant inhibitory effects even after 12 hr on cerulein-stimulated pancreatic exocrine secretion. These results indicate that FK480 is a potent, competitive, and specific CCK receptor antagonist on the exocrine pancreasin vivo, having oral bioavailability and a long biological half-life.
Similar content being viewed by others
References
Walsh JH: Gastrointestinal hormones.In Physiology of the Gastrointestinal Tract. LR Johnson (ed). New York, Raven, 1987, pp 181–253
Niederau C, Liddle RA, Ferrell LD, Grendell JH: Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis. J Clin Invest 78:1056–1063, 1986
Tani S, Itoh H, Koide M, Okabayashi Y, Otsuki M: Involvement of endogenous cholecystokinin in the development of acute pancreatitis induced by closed duodenal loop. Pancreas 8:109–115, 1993
Abbruzzese JL, Gholson CF, Daugherty K, Larson E, DuBrow R, Berlin R, Levin B: A pilot clinical trial of cholecystokinin receptor antagonist MK-329 in patients with advanced pancreatic cancer. Pancreas 7:165–171, 1992
Beglinger C, Dill S, Meyer B, Werth B, Adler G: Treatment of biliary colic with loxiglumide. Lancet 2:167, 1989
Meier R, Thumshirn M, Meyer B, Rovati LC, Gear K, Beglinger C: Treatment of chronic constipation in geriatric patients with loxiglumide, a cholecystokinin antagonist. Gastroenterology 98:A374, 1990
Read NW: The rational use of CCK antagonists in irritable bowel syndrome.In Cholecystokinin Antagonists in Gastroenterology; Basic and Clinical Status. G Adler, C Beglinger (eds). Heidelberg, Springer-Verlag, 1991, pp 214–219
Berlin RG, Freidinger RM: Characterization of MK-329.In Cholecystokinin Antagonists in Gastroenterology; Basic and Clinical Status. G Alder, C Beglinger (eds). Heidelberg, Springer-Verlag, 1991, pp 71–79
Niederau M, Niederau C, Strohmeyer G, Grendell JH: Comparative effects of CCK receptor antagonists on rat pancreatic secretionin vivo. Am J Physiol 256:G150-G157, 1989
Akiyama T, Otsuki M: Characterization of a new cholecystokinin receptor antagonist FK480in vitro isolated rat pancreatic acini. Pancreas 1994 (in press)
Ito H, Sogabe H, Nakarai T, Kadowaki M, Tokoro K, Tomoi M, Yoshida K: FK480: A novel CCK-A receptor antagonist. Jpn J Pharmacol 581(suppl 1):130p, 1992 (abstract)
Green GM, Taguchi S, Friestman J, Chey WY, Liddle RA: Plasma secretin, CCK, and pancreatic secretion in response to dietary fat in the rat. Am J Physiol 256:G1016-G1021, 1989
Shiratori K, Shimizu K, Watanabe S, Takeuchi T, Moriyoshi Y: Effect of CCK receptor antagonists CR1409 and CR1505 on rat pancreatic exocrine secretionin vivo. Pancreas 4:744–750, 1989
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with Folin-phenol reagent. J Biol Chem 193:265–275, 1951
Iwamoto Y, Yamamoto R, Kuzuya T: CR-1409: A potent inhibitor of cholecystokinin-stimulated amylase release and cholecystokinin binding in rat pancreatic acini. Pancreas 2:85–90, 1987
Otsuki M, Okabayashi Y, Nakamura T, Fujii M, Tani S, Fujisawa T, Baba S: Effects of new nonpeptide cholecystokinin antagonists L-364,718 and CR1392 on cholecystokinin stimulation of exocrine rat pancreas. Biomed Res 9:429–436, 1988
Otsuki M, Fujii M, Nakamura T, Okabayashi Y, Tani S, Fujisawa T, Koide M, Baba S: Loxiglumide, a new proglumide analog with potent cholecystokinin antagonistic activity in the rat pancreas. Dig Dis Sci 34:857–864, 1989
Evans BE, Block MG, Rittle KE, DiPardo RM, Whitter WL, Veber DF, Anderson PS, Fridinger RM: Design of potent orally effective nonpeptide hormone cholecystokinin antagonists. Proc Natl Acad Sci USA 83:4918–4922, 1988
Nagain C, Galas MC, Lignon MF, Rodriguez M, Martinez J, Roze C: Synthetic CCK8 analogs with antagonist activity on pancreatic receptors:In vivo study in the rat, compared to non-peptidic antagonists. Pancreas 6:275–281, 1991
Tani S, Otsuki M, Itoh H, Fujii M, Nakamura T, Oka T, Baba S: Histologic and biochemical alterations in experimental acute pancreatitis induced by supramaximal caerulein stimulation. Int J Pancreatol 2:337–348, 1987
Robert A, Lum JT, Lancaster C, Olafsson AS, Kolbasa KP, Nezamis JE: Prevention by prostaglandins of caerulein-induced pancreatitis in rats. Lab Invest 60:677–691, 1989
Setnikar I, Chiste R, Makovec F, Rovati LC, Warrington SJ: Pharmacokinetics of loxiglumide after single intravenous or oral doses in man. Arzneim Forsch Drug Res 38:716–720, 1988
Author information
Authors and Affiliations
Additional information
This work was supported in part by a grant from the Japanese Ministry of Health and Welfare (Intractable Disease of the Pancreas).
Rights and permissions
About this article
Cite this article
Tachibana, I., Otsuki, M. Effects of a new benzodiazepine derivative cholecystokinin receptor antagonist FK480 on pancreatic exocrine secretion in anesthetized rats. Digest Dis Sci 39, 1321–1328 (1994). https://doi.org/10.1007/BF02093800
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02093800