The plasma concentration, distribution, metabolism and excretion of ¹⁴C-Y-25130 were investigated in rats after intravenous administration.
1. Plasma levels of radioactivity (¹⁴C) decreased multiexponentially at the dose levels of 0.4, 1, 2, 10mg/kg, and the terminal half-lives (t_1/2z) were 8.4 -9.5 hours. No dose or sex differences in t_1/2z were observed. The areas under the plasma level-time curve were approximately proportional to the dose. Tissue levels of ¹⁴C were high in the liver, lung, kidney, pituitary gland, submaxillary gland, pancreas, stomach, adrenal, bone marrow, thyroid and spleen. Radioactivity rapidly disappeared from all tissues and was not detected in carcasses 96 hours after administration, suggesting no accumulation of ¹⁴C.
2. Binding rates of ¹⁴C to plasma proteins were 42.8-44.6% during 0.25-2 hours after administration.
3. Four days after administration to male rats at a dose of 1 mg/kg, urinary and fecal excretion of ¹⁴C were 45.5% and 52.9% of administered dose, respectively. At this dose, urinary excretion was much higher in female rats than in male rats. The excretion in male rats increased significantly at the highest dose level. Unchanged drug was found mainly in urine, while the unchanged drug, M1 and M3 were present in feces. The amount of unchanged drug in urine was much higher in female rats than in male rats. This amount increased at the highest dose level in male rats.
4. Fourty eight hours after administration to bile-duct cannulated male rats, 42.0% of the dose was excreted in bile and 12.8% in feces. This result indicates that another direct excretion route to the gastrointestinal tract exist besides the bile. About 13% of ¹⁴C excreted in bile was reabsorbed from the intestines by the enterohepatic circulation.

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1. Metabolism of Y-25130 was in vestigated in dogs after intravenous administration of ¹⁴C-labeled drug. Four metabolites were detected together with the unchanged drug in urine, feces and plasma. The main metabolites in urine were M1, M2 and M4, while in the feces the main metabolites were M1 and M5. The metabolite M3, previously found in rats, was not detected in any samples of dogs.
2. M1, M2, M4 and M5 from dog urine and M3 from rat urine were isolated and purified. These metabolites were identified by comparison of their nuclear magnetic resonance and mass spectra with those of authentic samples. Y-25130 was metabolized by oxidative N-demethylation, the N-oxidation of an azabicyclooctane ring, the combination of the above two reactions, the cleavage of an oxazine ring and the hydroxylation of a benzene ring.

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After oral administration of (pivaloyloxymethyl-¹⁴C) ME1207 to rats, the radioactivity derived from the oxymethylene moiety in the ester group was well absorbed and the absorption extent was more than 90% of administered dose.
The radioactivity was mainly excreted with expired air as the ¹⁴CO₂. The cumulative excretion with expired air within 168hr accounted to 67.9% of the dosed radioactivity.
The tissue levels of the radioactivity were high and prolonged in most tissues, especially in the bone marrow, intestinal mucosa, pancreas and Harderian gland.

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The metabolism of ME1207, a new oral esterified cephem of ME1206, was studied in rats and dogs.
When ME1207 was administered orally to rats, the ME1207 was isomerized slightly to ME 1207E and ME1207Δ³ in gastro-intestinal tract. The ME1206E and ME1206Δ³ were found in the plasma in trace amount in addition to ME1206, the main compound, after oral administration of ME1207. We assumed that these isomers of ME1206 originated from those of ME1207, formed in the gastro-intestinal tract.
The metabolites in the urine and feces after oral administration of (Aminothiazole-2-¹⁴C) ME1207 to rats and dogs were analyzed by radio-HPLC. ME1206 was mainly excreted in the urine in rats and dogs. MOH, the degraded product which is formed by the opening of the β-lactam ring of ME1206, was mainly excreted in the feces in rats. On the other hand, ME 1206, ME1207, ME1206E, ME1206Δ³ and M_OH were excreted in the feces in dogs.
Pivalic acid, the metabolite derived from the ester moiety of ME1207, was detected in the urine in a form of conjugate after oral administration of ME1207 to rats and dogs. Its urinary excretion ratio within 48hr was 58.17% and 50.68% of administered dose in rats and dogs, repectivly.

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The pharmacokinetic/pharmacodynamic model considering the effect of omeprazole, an anti-ulcer drug, on the metabolic turn-over of H⁺/K⁺ ATPase (proton pump) was developed. The pharmacokinetic and pharmacodynamic parameters of omeprazole were calculated based on the plasma concentration profile and the inhibition ratio of gastric acid secretion after single oral administration of omeprazole at the dose of 40mg.
Reaction rate constant of omeprazole with proton pump and the elimination rate constant of PP were 1.2 M^-1·hr^-1 and 0.0243hr-¹, respectively. Simulation profiles of inhibition ratio of gastric acid secretion after single and repeated oral administration of omeprazole are consistent with the data reported by other investigators. Dose-response curve shifted to a lower dose after repeated administration of omeprazole, as compared with that after single administration. The correlation between the clearance of metabolic turn-over of proton pump and the body weight seems to follow Adolph's power law, suggesting the possibility of prediction of human's therapeutic dose of omeprazole from animal data.

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The organ and tissue distribution of radioactivity, the concentration of acidic and basic metabolites in plasma, brain and liver were studied after intravenous administration of ¹⁴C-clentiazem at a dose of 3mg/kg to male and female rats. The plasma levels of radioactivity was higher in male rats than in female rats at any time examined. On the other hand, the radioactivity in the organs and tissues became higher in female rats than that in male rats with the lapse of time. The acidic metabolites which might be formed through oxidative deamination of clentiazem and the basic metabolites were higher in the plasma of male rats. The metabolites in the brain were mainly of basic character and the levels were higher in female rats. Few acidic metabolites were found in the brain of both male and female rats. One may expect that basic metabolites were easily transferred to the organs and tissues, while acidic metabolites were hardly transferred, due to their pKa values if the pH -partition theory is considered. Accordingly, it would be considered that plasma levels of radioactivity were higher in male rats while the organ and tissue levels of radioactivity were higher in female rats.

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The tissue distribution of radioactivity and the presence of metabolites in plasma and brain were studied in male and female rats after single and consecutive oral administration of ¹⁴C-clentiazem at a dose of 30mg/kg. The plasma levels of radioactivity in male and female rats attained steady levels since the third day after starting dosage. The organ and tissue levels of radioactivity in male rats at 1 and 6hr after single and consecutive administration were lower than those in female rats, but became higher at 24 and/or 72hr. The plasma concentrations of the acidic metabolites were higher in the male rats and those levels were raised by the consecutive administration, however, few acidic metabolites in the brain were found. Basic metabolites were more abundant in the brain and the level of the basic ones were higher in the female rats. The basic metabolite in the plasma and brain was mainly MB1 in the both sexes.

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The binding of clentiazem to human plasma protein and to three purified proteins were measured in vitro. The effect of interaction with various other drugs, which might be used for combined therapy, on the binding of clentiazem was also measured. The percentage of clentiazem bound to human plasma protein was found to be constant (ca. 90%) at the concentration range of 20 ?? 10, 000ng/ml. It would be thought that clentiazem was mainly bound to the albumin fraction of plasma and the binding characteristics of clentiazem to albumin was non-specific. No interference of the various other drugs on the binding of clentiazem to plasma protein were found.

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The metabolism of (±)-3-(benzylmethylamino)-2, 2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate hydrochrolide (TC-81) was studied in male rats and dogs after a single oral administration of ¹⁴C-TC-81 or d₃-TC-81.
The fifteen metabolites of TC-81 were identified by gas-chromatography mass-spectrometric method and/or TLC and HPLC.
In rats urine, M-7 or M-12 were found as m ajor metabolites and their content was estimated to be about 1.0% of dose for 24hr after dosing. In rats bile, M-11 was found as a major metabolite and its content was estimated to be about 10.4% of dose for 48hr after dosing. In rat plasma, M-4 and M-6 were found as metabolites. M-4 was eliminated from plasma monophasically (t_1/2 was from 1.0hr to 2.6hr), but M-6 was eliminated from plasma biphasically (t_1/2(α) was from 2.7hr to 7.7hr and t_1/2(β)was from 42.7hr to 58.0hr). In dogs urine, M-14 was found as a major metabolite and its content was estimated to be about 4.3% of dose for 24hr after dosing.
The proposed metabolic pathways of TC-81 were 1)oxidation of the dihydoropyridine moiety to the pyridine form, 2) metabolism the side chain at the 3-position, 3) hydrolysis the methyl ester at the 5-position, 4) hydroxylation of methyl group at 2- or 6-position, 5)conjugation and 6)defluorination.

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