Stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor, in extensive and poor metabolizers of S-mephenytoin.

Pantoprazole, a proton pump inhibitor, is administered as a racemic mixture. To determine the role of cytochrome P450 (CYP) 2C19 in the stereoselective metabolism of pantoprazole, we investigated the pharmacokinetic disposition of (+)- and (-)-pantoprazole in 7 extensive metabolizers and 7 poor metabolizers of S-mephenytoin. All of the subjects received an oral 40-mg dose of racemic pantoprazole as the enteric-coated formulation. In the extensive metabolizers, the mean clearance of (-)-pantoprazole was only slightly lower than that of (+)-pantoprazole and no significant differences in the other pharmacokinetic parameters between (+)- and (-)-pantoprazole were observed. The mean (+)/(-) ratios for maximum concentration, area under the plasma concentration-time curve from 0 to infinity, and elimination half-life were 0.94, 0.82, and 0.90, respectively. In contrast, in the poor metabolizers, the clearance values of both enantiomers were significantly lower than those in the extensive metabolizers, and a significant difference in pharmacokinetics between (+)- and (-)-pantoprazole was observed. The mean elimination half-life for (+)-pantoprazole was 3.55-fold longer than that of (-)-pantoprazole, and the mean maximum concentration and area under the plasma concentration-time curve from 0 to infinity for (+)-pantoprazole were 1.31- and 3.59-fold greater, respectively, than those for (-)-pantoprazole. These results indicate that the stereoselective metabolism of pantoprazole depends on S-mephenytoin 4'-hydroxylase (CYP2C19). The metabolism of (+)-pantoprazole was impaired to a greater extent than (-)-pantoprazole in the poor metabolizers.

Metabolic disposition of pantoprazole, a proton pump inhibitor, in relation to S-mephenytoin 4'-hydroxylation phenotype and genotype.

OBJECTIVES: To assess the possible relationship between the metabolic disposition of pantoprazole and genetically determined S-mephenytoin 4'-hydroxylation phenotype and genotype. METHODS: The pharmacokinetic disposition of pantoprazole was investigated in 14 Japanese male volunteers (seven extensive and seven poor metabolizers of S-mephenytoin). All subjects received a single 40 mg oral dose of pantoprazole as the enteric-coated formulation. RESULTS: An interphenotypic difference in the metabolic disposition of pantoprazole was observed: the mean values for area under the concentration-time curve (AUC), elimination half-life (t1/2), and apparent oral clearance were significantly (p < 0.01) greater, longer, and lower, respectively, in the poor metabolizers than in the extensive metabolizers. The mean AUC of pantoprazole sulfone was greater (p < 0.01) in the poor metabolizers than in the extensive metabolizers, whereas the mean AUC of the main demethylated metabolite (M2) was lower (p < 0.01) in the poor metabolizers than in the extensive metabolizers. A significant negative correlation was observed between the individual values for log10% urinary excretion of 4'-hydroxymephenytoin and AUC of pantoprazole (rs = -0.816; p < 0.005). The CYP2C19 genotyping test results were found to be in a complete accordance with the phenotypes. CONCLUSION: These data indicated that the metabolic disposition of pantoprazole is under the pharmacogenetic control of S-mephenytoin 4'-hydroxylase (CYP2C19).

Pharmacokinetics and tolerance of pantoprazole, a proton pump inhibitor after single and multiple oral doses in healthy Japanese volunteers.

The pharmacokinetics and tolerance of pantoprazole were investigated after single (20, 40, 80, and 120 mg) and multiple (80 mg once a day for 7 days) oral administration as enteric-coated tablet formulation to healthy male Japanese volunteers. Pantoprazole was well tolerated with no serious adverse events at all doses. Pantoprazole was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 1.77-9.25 micrograms/ml for the 20-120 mg dose and the mean time to reach Cmax (tmax) ranged from 1.92-2.42 h. The half-life (t1/2) ranged from 0.74-1.16 h. A good linear correlation was found between the administered doses (20-120 mg) and the resulting area under the concentration-time curve (AUC) and Cmax with the correlation coefficients of 0.9088 and 0.9263, respectively. Within 24 h, pantoprazole was excreted into urine as the unchanged drug to a negligible extent. In the multiple dose study, 2 apparent poor metabolizers (PMs) of pantoprazole were observed. The means of Cmax, AUC and t1/2 for these 2 PMs were 1.6, 6.7, and 6.8 times higher than those of the extensive metabolizers (EMs). The pharmacokinetic parameters such as Cmax, AUC, and t1/2 after the 7th oral dose were not significantly different from those after the 1st dose both in the PMs and the EMs, which indicated that there was virtually no drug accumulation.

DQ-2511, having an antiulcer action, elicits vasodilation through an increase in cyclic GMP contents in rat arteries.

It has been reported that 3-(([2-(3,4-dimethoxyphenyl)ethyl]carbamoyl)methyl)amino-N-methylbenz amide (DQ-2511: ecabapide) effectively increases gastric mucosal blood flow in rats, suggesting that this property may contribute to the antiulcer activity. To clarify the mechanisms underlying the increase in gastric mucosal blood flow, we investigated the dilator response of rat isolated thoracic aorta, mesenteric artery and celiac artery smooth muscle preparations to DQ-2511. This compound prevented noradrenaline-induced contraction in both the presence and absence of endothelium in the arterial specimen, and it (0.01-1 mM) inhibited these contractions induced by noradrenaline in all tissues in a concentration-dependent manner. This inhibitory effect of DQ-2511 was most evident in the celiac artery. The dilator response to DQ-2511 (0.1 mM) was abolished after pretreatment with methylene blue (3 microM), a guanylate cyclase inhibitor. Under the same conditions, methylene blue inhibited the dilator response to acetylcholine (1 microM), but not that to papaverine (10 microM). Furthermore, when DQ-2511 (0.01-1 mM) was incubated with the arterial preparations, this compound increased cyclic GMP content in segments in a concentration-dependent manner. These findings demonstrate that the vasodilation induced by DQ-2511 is independent of the endothelium and is related to the augmentation of intracellular cyclic GMP content, which may consequently contribute to the increased gastric mucosal blood flow.

Cardiovascular properties of the new anti-ulcer drug 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]-amino-N- methylbenzamide.

Cardiovascular activities of 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]-amino-N- methylbenzamide (DQ-2511, CAS 104775-36-2), an anti-ulcer drug, were investigated in anesthetized dogs and conscious rats. In anesthetized and laparotomized dogs, DQ-2511 at intravenous doses of 5-50 mg/kg dose-relatedly induced an increase in celiac and mesenteric arterial blood flow, and a decrease in their resistance, whereas the drug had little or no effect on carotid and renal blood flow. DQ-2511 increased cardiac contractility in anesthetized dogs at an intravenous dose of 15 mg/kg. In addition to this effect, it produced an increase in respiratory rate, a decrease in blood pressure and a slight increase in heart rate after dosing at 50 mg/kg. The drug had little or no effect on femoral blood flow and produced no significant changes in the electrocardiogram. In conscious rats, blood flow in gastrointestinal organs was compared with flow in other organs using the microsphere method. Blood flow in the stomach, duodenum, ileum, pancreas, spleen, and kidney tended to decrease in the vehicle-treated control group. DQ-2511, at an oral dose of 100 mg/kg, significantly increased blood flow in the stomach, duodenum and spleen, and tended to increase flow in the pancreas, testis and fat in comparison with the vehicle-treated control group. Blood flow in the liver, heart and skeletal muscle tended to decrease, whereas the other regional blood flows did not differ from those in the control group. DQ-2511 at this oral dose had little or no effect on blood pressure, heart rate, cardiac output and total peripheral resistance in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and antiallergy activity of [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9 (3H)-one derivatives. I.

A series of 6-substituted [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one derivatives 4a--z were synthesized from 5-substituted 1,3,4-thiadiazol-2-amines 5 by the following consecutive reactions: pyrimidine ring closure with bis(2,4,6-trichlorophenyl) malonate, nitration, chlorination, amination, hydrogenation and diazotization. The structure of 4 was confirmed by an alternate synthesis of 4, involving reaction of 5-substituted 2-azido-1,3,4-thiadiazole 13 with ethyl cyanoacetate, followed by the Dimroth rearrangement and ring closure. The antiallergic activities (anti-passive peritoneal anaphylaxis, anti-passive cutaneous anaphylaxis and anti-slow reacting substance of anaphylaxis activities) of the products were evaluated.

Antiulcer effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl] carbamoyl]methyl]-amino-N-methylbenzamide in experimental gastric and duodenal ulcers.

Effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl] methyl]-amino-N-methylbenzamide (DQ-2511), a newly synthesized compound, were evaluated using various types of experimental gastric and duodenal ulcers in rats. Pretreatment with DQ-2511, over the dose range 30-300 mg/kg p.o., resulted in a dose-related inhibition of water-immersion stress-, serotonin-, acetylsalicylic acid (ASA)-, indometacin-, ethanol-, and 2-deoxy-D-glucose(2DG) plus indometacin-induced gastric ulcers as well as cysteamine-induced duodenal ulcers. The antiulcer potencies of DQ-2511 were equal to or greater than those of H2-receptor antagonist cimetidine in these ulcer models except for ASA- and 2DG plus indometacin-induced ulcers. The rate of healing of chronic gastric ulcers induced by acetic acid was significantly accelerated by DQ-2511 (100 and 300 mg/kg p.o.) but not by the same doses of cimetidine. DQ-2511, at doses of 30 mg/kg p.o. and above, produced a significant decrease in gastric acid and pepsin output in pylorus-ligated rats. In anesthetized rats with acute gastric fistulae, 30 mg/kg i.v. of DQ-2511 significantly inhibited gastric acid secretion stimulated by 2DG, whereas it did not affect gastric hyperacidity evoked by either carbachol, histamine or pentagastrin. At effective antiulcer doses, this compound produced a sustained increase in gastric mucosal blood flow in conscious, restrained rats. Based on these observations, DQ-2511 is characterized as a new antiulcer compound with beneficial effects on both gastric aggressive and defensive factors. Furthermore, these results indicate a possible superiority of DQ2511 over cimetidine in regard to its antiulcer potency and spectrum.

Antihypertensive and general pharmacological properties of budralazine.

Antihypertensive and general pharmacological properties of 1-[2-(1,3-dimethyl-2-butenylidene)hydrazino]phthalazine (budralazine) were studied in comparison with those of hydralazine. Single oral administration of budralazine (4--15 mg/kg) to DOCA/saline hypertensive rats resulted in a dose-related and sustained antihypertensive effect which was 2--3 times less potent than that of hydralazine. However, there were no remarkable differences between both drugs in the hypotensive magnitude after the 4-week treatment of spontaneously hypertensive rats (SHR) with their higher doses. After single oral administration, budralazine was about 8 times less potent than hydralazine in increasing plasma renin activity in normotensive rats. At effective antihypertensive doses, budralazine inhibited spontaneous motor activity (mice), gastrointestinal propulsion (mice), gastric emptying rate (rats), gastric secretion (rats), urine output and urinary electrolyte excretion (rats) as well as carrageenan-induced paw edema formation (rats), which were essentially less potent than those produced by hydralazine. Budralazine at 6 mg/kg i.v. exhibited a slowing of neocortical EEG (cats) and a slight increase in spinal monosynaptic potentials (cats) and inhibited gastrointestinal motility (dogs). The same dose of hydralazine produced an increase in occurrence of the neocortical fast waves, an inhibition of the monosynaptic potentials and the carotid sinus reflex (dogs) and a stimulation of intestinal motility followed by prolonged and marked reduction. Budralazine (10(-5) g/ml) slightly potentiated contractile response of isolated guinea-pig vas deferens to noradrenaline, whereas hydralazine (10(-4) g/ml) inhibited the response. Budralazine (10(-5) g/ml), like hydralazine (10(-4) g/ml), produced a nonspecific antagonism against the contractile response of isolated guinea-pig ileum to various spasmogens, and both drugs (10(-4) g/ml) reduced either spontaneous motility or oxytocin-induced motility in isolated rat uterus.