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A radioimmunoassay was developed for a new, potent inhibitor of angiotensin-converting enzyme (ACE; EC 3.4.15.1), calcium(-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methyl- propionyl]-L-prolinate (MC-838, altiopril calcium). The antiserum was obtained by immunizing rabbits with MC-838-bovine serum albumin (BSA) conjugate. MC-838-L-tyrosine labeled with 125I and purified by thin-layer chromatography was used as a tracer. The assay sensitivity was 0.1 ng/ml, the average intra-assay coefficient of variation was 7.9%, and the average inter-assay coefficient of variation was 13.7%. The antiserum was specific for MC-838, showing only slight crossreactivity with degradation products of MC-838. After a single oral dose of MC-838 (2 mg/kg), radioimmunoassay of MC-838 canine serum demonstrated rapid absorption from the gastrointestinal tract with a peak level of 40.6 ng/ml. The decline in serum concentration was a biphasic decay, with a half-life of 80 min during rapid falloff followed by a slower decline.

The effects of equihypotensive doses of nicorandil and verapamil on plasma digoxin concentrations have been assessed in rats and dogs. In a single digoxin dose study, digoxin (1 mg kg−1) alone, or in combination with nicorandil (5 mg kg−1) or verapamil (25 mg kg−1) was given orally to rats. When given chronically to rats, a single dose of digoxin (1 mg kg−1) orally for 7 consecutive days was followed, on day 8, by digoxin alone, or together with nicorandil (5 mg kg−1) or verapamil (25 mg kg−1). In dogs, a loading dose of digoxin (50 μg kg−1) was given orally on day 1, then 25 μg kg−1 was administered for the following 6 days. On day 8, digoxin (50 μg kg−1) was given with nicorandil (5 mg kg−1) or verapamil (20 mg kg−1). In rats, the AUC0–24 and Cmax of plasma digoxin were enhanced significantly by coadministration of verapamil, but not by nicorandil. In dogs, verapamil significantly increased the Cmax of plasma digoxin, but not the AUC. Nicorandil had no effect on either parameter.

The effects of nicorandil, N-(2-hydroxyethyl)nicotinamide nitrate (ester), in reducing systemic blood pressure (SBP) in rats were studied in comparison with isosorbide dinitrate and nitroglycerin. The drugs were administered to pentobarbitone-anaesthetized rats by jugular vein (i.v.), portal vein (p.v.), intrajejunal (i.j.), intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Nicorandil was absorbed rapidly through all routes, and caused marked hypotension dose-dependently. With isosorbide dinitrate and nitroglycerin, unlike nicorandil, the p.v. dose required to induce a vasodepressor response was significantly greater than that required to cause a comparable response after i.v. administration. In non-recirculating rat liver perfusion experiments, nicorandil was reduced only 5–10% during a single passage through the liver, while nitroglycerin was reduced over 95%. In recirculating liver perfusion experiments, the progressive decrease of nicorandil in the blood recirculated was accompanied by a corresponding increase of SG-86, a denitrate compound of nicorandil (its main metabolite). Sixty min after dosing, nicorandil was decreased by approximately 73% of the initial nicorandil blood concentration and SG-86 was increased by approximately 70%. The extent of degradation of nicorandil in liver homogenates, examined by thin-layer chromatography, was in the following order: rat = guinea-pig > dog = monkey > pig. In these species a close inverse relationship is apparent between the rate of liver nicorandil degradation and hypotensive effects of nicorandil.

1,5-Anhydroglucitol (1-DG) has been known as an antimetabolic glucose analogue. Using gas chromatography, 1-DG was found to be physiologically present in rat serum. In order to investigate its direct and long-term effects on feeding, 1-DG was infused during the light period into the rat third ventricle in doses of 3.0, 6.0 and 12.0 mumol/rat. Its effects were then compared to those of similarly applied 2-deoxy-D-glucose (2-DG). Following initial hyperphagia, both of these glucose-analogues produced suppressive effects on feeding during the subsequent day throughout the light and dark periods. On the third day after 2-DG injection reduction of feeding did not recover completely to the pretreatment baseline levels, but it did recover after 1-DG. Both 1-DG and 2-DG caused linear dose-related hypophagia, with the slope for 1-DG being about half of that for 2-DG. It is suggested that the delayed hypophagia which followed the initial hyperphagia produced by deoxyglucose was a result of sustained inactivation of the Na-pump due to intracellular ATP deficiency caused by accumulation of deoxy-glucose-6-phosphate.

The critical dissolution pH values for forty-eight enteric-coated tablets of pyridoxal phosphate (PAL-P) commercially available in Japan were determined by using an oscillating basket apparatus with buffers of various pH. The tablets were divided into three groups according to their critical dissolution pH (pH

Studies on the activity of the glucuronic acid pathway in alloxan diabetic rabbits were carried out. Amount of D-glucaric acid, L-ascorbic acid, and D-glucuronic acid in urine increased in the case of the alloxan diabetic rabbits. The transformation from D-glucuronolactone to D-glucaric acid was higher than normal in the diabetic animals. The expired 14-CO2 decreased and urinary excretion of labeled L-gulonic acid increased after administration of 6-14-C-glucuronolactone in the diabetic rabbits. L-Gulonic acid dehydrogenase, lactonase II, and beta-glucuronidase activities were reduced, and UDPGA-pyrophosphatase, D-glucuronic acid-1-phosphatase, and UDPGA-transferase activities increased in the diabetic rabbit liver. From these results, it may be concluded that an increase of endogenous D-glucuronic acid in the diabetic states could be attributed to a metabolid defect in the step of L-gulonic acid dehydrogenation and to the enhancement of UDPGA-pyrophosphatase and D-glucuronic acid-1-phosphate phosphatase activities.

The pepsinogen gene is hypomethylated in the stomach, in which it is expressed. For demonstration that this hypomethylation of the pepsinogen gene in the stomach reflects pepsinogen-producing cells, we analyzed fractions of dispersed mucosal cells with various contents of pepsinogen-producing cells prepared from guinea pig stomach by centrifugal elutriation. mRNA expression and the extent of hypomethylation of the pepsinogen gene in each fraction was closely correlated with the content of pepsinogen-producing cells. These results suggested hypomethylation of the pepsinogen gene in pepsinogen-producing cells and differential pepsinogen gene methylation in cell subpopulations in the stomach.

The bioavailability of five enteric-coated tablets and one sugar-coated tablet of pyridoxal phosphate previously tested in humans was studied in beagle dogs, and the dissolution rates of the tablets were measured by various dissolution methods. The results in beagle dogs correlated significantly with those in humans, and beagle dogs can therefore be used as an animal model to predict the bioavailability in humans of enteric-coated tablets of pyridoxal phosphate. On the other hand, dissolution tests were not as useful as the bioavailability test in beagle dogs. Only the dissolution parameter obtained by the oscillating basket method using medium of pH 5.9 correlated significantly with the initial excretion rates of pyridoxic acid found in the human study. The oscillating basket method with pretreatment in the No. 1 medium (J. P. IX) failed to reject tablets having inferior bioavailabilities in humans. Pretreatment with acidic solution in dissolution or disintegration tests was considered to make the prediction of bioavailability less reliable.

The effects of AN-132, 3-(diisopropylaminoethylamino)-2′,6′-dimethylpropionanilide.2H3PO4, on chloroform-induced arrhythmias and plasma digoxin concentrations have been compared with those of quinidine in rats. AN-132 (0.01–3 mg kg−1) administered orally significantly inhibited the incidence of cardiac arrhythmias in a dose-related fashion. A single dose of digoxin (1 mg kg−1) given orally for 7 consecutive days was followed, on day 8, orally by digoxin alone, or together with AN-132 (50, 100 and 200 mg kg−1) or quinidine (25 and 50 mg kg−1). The AUC0-24 and Cmax of plasma digoxin were enhanced significantly by co-administration of quinidine, but not by AN-132.

SAKAI, K., AONO, J., SHIRAKI, Y., HINOHARA, Y., AKAMATSU, A., TANAKA, S. and KUROMARU, K. MC-838 (Altiopril Calcium): A Novel Orally Active Angiotensin Converting Enzyme Inhibitor. Tohoku J. exp. Med., 1987, 152 (4), 363-374 - MC-838, calcium (-)-N-[(S)-3-(N-cyclohexylcarbonyl-D-alanyl) thio-2-methylpropionyl]-L-prolinate, is a new orally active angiotensin converting enzyme (ACE) inhibitor in which the mercapto-group is taken up in a stable thiolester linkage. The linkage was relatively resistant against enzymatic hydrolysis by rat liver homogenates. The ACE prepared from rabbit lung was inhibited by MC-838 in a concentration-dependent manner. In isolated rat aortic ring and guinea-pig ileum preparations, MC-838 was highly specific in suppressing the contractile response to angiotensin-I (A-I) and in augmenting the contractile one to bradykinin. However, the ACE inhibitory activity of MC-838 was 30-100 times less potent than that of captopril. In conscious two-kidney (2 KG), renal hypertensive rats and spontaneously hypertensive rats (SHRs), MC-838 (3 and 10 mg/kg) given orally caused a long-lasting hypotensive effect with a slow onset. When compared on a weight basis (3mg/kg), the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action of MC-838 was approximately 2 times longer than that of captopril.