Sulphonated aluminium phthalocyanine (SALPC) photodynamic action induces amylase secretion and permanent calcium oscillation in rat pancreatic acinar cells, because of the activation of phospholipase C or signalling proteins upstream. The aim of the present study was to investigate the involvement of muscarinic acetylcholine and cholecystokinin (CCK) receptors.

Muscarinic receptor antagonist atropine (10 μM) blocked amylase secretion induced by bethanechol (100 μM), and CCK1 receptor antagonist (S)‐N‐[1‐(2‐fluorophenyl)‐3,4,6,7‐tetrahydor‐4‐oxo‐pyrrolo‐[3,2,1‐jk][1,4] benzodiazepine‐3yl]‐1H‐indole‐2‐carboxamide (FK480) (1 μM) blocked amylase secretion induced by CCK (100 pM).

Amylase secretion induced by SALPC photodynamic action was not inhibited when atropine and FK480 were present during photodynamic action. However, addition of FK480 1 μM after initiation of photodynamic action inhibited photodynamic amylase secretion. Bethanechol (10, 100 μM) added after photodynamic action resulted in a full secretory response.

Atropine (10 nM) abolished calcium oscillation induced by bethanechol (5 μM), and FK480 (10 nM) blocked calcium oscillation induced by CCK (10 pM).

Atropine up to 10 μM was without effect on Ca2+ oscillation triggered by photodynamic action, but these oscillations were abolished by FK480 (10 nM). FK480 (10 nM) had no effect on calcium oscillations induced by bethanechol (5 μM). Bethanechol 5 μM, added after FK480 blockade of photodynamic calcium oscillation, still triggered regular calcium oscillation.

It is concluded that SALPC photodynamic action selectively and permanently activates CCK receptor in rat pancreatic acini. Such permanent and selective modulation of signalling proteins has important implications for the treatment of pancreatitis, prion diseases, and neurodegenerative disorders.

British Journal of Pharmacology (2003) 139, 872–880. doi:10.1038/sj.bjp.0705295

01 May 2003·Drug Metabolism and DispositionQ2 · MEDICINE

Utility of Hepatocytes in Predicting Drug Metabolism: Comparison of Hepatic Intrinsic Clearance in Rats and Humans in Vivo and in Vitro

Q2 · MEDICINE

Article

Author: Naritomi, Yoichi ; Terashita, Shigeyuki ; Kagayama, Akira ; Sugiyama, Yuichi

We investigated hepatic in vitro intrinsic clearance (CL(int,in vitro)) in freshly isolated or cryopreserved hepatocytes and compared with CL(int,in vivo) by using nine model compounds, FK1052, FK480, diazepam, diltiazem, troglitazone, quinotolast, FK079, zidovudine, and acetaminophen, in rats and humans. The compounds showed a broad range of in vivo hepatic extraction ratios (rat, 0.05-0.93; humans, 0.03-0.76) and were metabolized by hepatic P450, UDP-glucuronosyltransferase, sulfotransferase, and/or esterase. CL(int,in vitro) was determined from substrate disappearance rate at 1 microM in hepatocytes. CL(int,in vivo) was calculated from in vivo pharmacokinetic data using two frequently used mathematical models (the well stirred and dispersion models). When estimating rat CL(int,in vitro) in freshly isolated hepatocytes, the rat scaling factor values (CL(int,in vivo)/CL(int,in vitro)) showed marked difference among the model compounds (0.2-73.1-fold). The rat CL(int,in vitro) values in freshly isolated hepatocytes were in good agreement with these in cryopreserved hepatocytes. Human CL(int,in vitro) were determined by use of cryopreserved hepatocytes. When human CL(int,in vitro) was regarded as the predicted CL(int,in vivo), the observed and predicted CL(int,in vivo) for FK1052, FK480, troglitazone, and FK079 differed markedly (12.4-199.0-fold). In contrast, using human CL(int,in vitro) corrected with the rat scaling factors yielded better predictions of CL(int,in vivo) that were mostly within 5-fold of the actual values. These results make the evaluation using hepatocytes more useful and provide a basis for predicting hepatic clearance using hepatocytes.

01 Feb 2002·Regulatory Peptides

Bovine pancreatic secretion in the first week of life: potential involvement of intestinal CCK receptors

Article

Author: Véronique Romé ; Christine Bernard ; Romuald Zabielski ; Jean Alain Chayvialle ; Jean Morisset ; Paweł Podgurniak ; Marzena Biernat ; Paul Guilloteau

The aim of this study was to evaluate pancreatic juice secretion of calves in the first postnatal days, and determine a potential involvement of cholecystokinin (CCK) and intestinal CCK receptor in its regulation. Nine neonatal Friesian calves (five controls and four treated intraduodenally with FK480, a CCK-A receptor antagonist) were surgically fitted with a pancreatic duct catheter and a duodenal cannula before the first colostrum feeding. Collections of pancreatic juice and duodenal luminal pressure recordings were started early after recovery from anaesthesia and continued for 6 days. From day 2 or 3 of life, periodic fluctuations in pancreatic secretions were observed in concert with duodenal myoelectric motor complex (MMC) and variations in plasma pancreatic polypeptide (PP) concentrations. Intraduodenal administration of FK480 reduced pancreatic juice secretion while intravenous infusion of CCK had no effect. Immunocytochemistry indicated an association of mucosal CCK-A and -B receptors with neural components of the small intestine. In conclusion, periodic activity of the exocrine pancreas exists in neonatal calves soon after birth and local neural intestinal CCK-A receptors could be partly responsible for the modulation of neonatal calf pancreatic secretion.

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatitis	Phase 2	-	Astellas Pharma, Inc.	-

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