1. We have examined the metabolism of diazepam by ten human cytochrome P450 forms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5) expressed in HepG2 cells using a recombinant vaccinia virus system. 2. Among the P450 forms tested, diazepam was significantly demethylated by CYP2B6, 2C9, 2C19, 3A4 and 3A5, with 2C19 exhibiting the highest rate at concentrations < 0.1 mM, and hydroxylated only by the latter three enzymes, with 3A5 being the most active. The N-demethylation activity of diazepam by 2C19 at a concentration of 20 microM was six times of that by 3A4. However, that by 2C9 was detected at only a trace level. 3. CYP2C19, 3A4 and 3A5 of the ten human P450s catalysed the 3-hydroxylation of nordiazepam, and 2B6, the 2C subfamily and the 3A subfamily catalysed the N-demethylation of temazepam. CYP3A4 exhibited the highest activity of nordiazepam 3-hydroxylation and temazepam N-demethylation. 4. Diazepam N-demethylation by human liver microsomes correlated with diazepam 3-hydroxylation, but not S-mephenytoin 4'-hydroxylation. 5. Our results suggest that in the human liver, the metabolism of diazepam to nordiazepam is mediated by CYP3A4, which has been reported as the most abundant P450 form in human liver as well as 2C19, which has been reported as a polymorphic enzyme.

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H ϩ ,K ϩ -ATPase activity in pig gastric vesicles with an acidic internal environment with an IC 50 of 0.28 M. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n ϭ 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED 50 values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n ϭ 6) at 0 to 2 h after administration (ED 50 ϭ 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED 50 ϭ 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was Ն4 for 17% (n ϭ 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n ϭ 4), 0.4 (n ϭ 8), and 0.8 mg/kg (n ϭ 5), the pH was Ն4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n ϭ 4) and 1.6 mg/kg (n ϭ 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n ϭ 6), E3710 increased the intragastric pH to Ͼ4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.

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(S)‐N‐(endo‐8‐Methyl‐8‐azabicyclo[3.2.1]oct‐3α‐yl)‐4‐amino‐5‐chloro‐2‐(1‐methyl‐2‐butynyloxy)[carbonyl‐14C]benzamide monohydrochloride (14C‐E3620, 1 1), which was required for a study of the pharmacokinetic profile of E3620, is not only a potent antagonist of 5‐HT3 receptors but also a potent agonist of 5‐HT4 receptors. It was synthesized using (S)‐5‐chloro‐4‐(2,5‐dimethylpyrrol‐1‐yl)‐2‐(1‐methyl‐2‐butynyloxy)[carboxy‐14C]benzoic acid (8) as the labelled starting material. © 1997 John Wiley & Sons, Ltd. The product was produced at high radiochemical purity with a specific activity of 2.02GBq / mmol.

14C‐Labelled (S)‐(+)‐6‐(2‐chlorophenyl)‐3‐cyclopropanecarbonyl‐8,11‐dimethyl‐2,3,4,5‐ tetrahydro‐8H‐pyrido[4′,3′:4,5]thieno[3,2‐f][1,2,4]triazolo[4,3‐a][1,4] diazepine (14C‐E6123), a platelet activating factor receptor antagonist for studying the pharmacokinetic profile of E6123, was synthesized in three steps using [1‐14C] acetyl hydrazine fumarate as the labelled starting material. The final product has high chemical and radiochemical purity with a specific activity of 53.2mCi per mmol (1.97GBq per mmol). The overall radiochemical yield is 6.0%.