The metabolism of trimebutine maleate (I), (±)-2-demethylamino-2-phenylbutyl 3, 4, 5-trimethoxybenzoate hydrogen maleate, was studied in dogs and man after oral administration of ¹⁴C-labeled I to beagle dogs and of nonlabeled I to human volunteers. Metabolites of I in the urine and plasma were fractionated, identified and quantified.
In both species, I was rapidly metabolized and the main urinary metabolites were alcoholic and acidic products of ester hydrolysis, N-demethylated metabolites, and conjugates : i. e., 2-dimethylamino-2-phenylbutanol (II) and its N-mono and di-demethylated metabolites (II and IV), 3, 4, 5-trimethoxybenzoic acid (V), and their conjugates. In dogs, most of the alcohol-moiety metabolites (III ≥ II > II, 60.1%) were excreted in conjugated from and the acid-moiety metabolite (V, 46.5%) in unconjugated form. In man, N-mono- and di-demethylated metabolites (VI, VII) of I retaining the ester bond were detected in a total amount corresponding to 0.3% of the administered dose. The alcohol-moiety metabolites (IV > III > II, 62.1 %) were excreted in both unconjugated (28.4%) and conjugated form (33.7%). The acid-moiety metabolite (V, 50.9%) was mainly excreted as the glucuronic acid conjugate (41.2 %) and only partly in unconjugated form (9.7%). In plasma, I and its N-demethylated metabolites (V1, VII) were detected in both species beside the urinary metabolites. Main plasma metabolites were V and the conjugates of the alcohol-moiety metabolites in dogs, and V and one (VI) of the demethylated metabolites of I in man.

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MGV-5 containing 4 electrolytes and polyethylene glycol 4000 (PEG 4000) is a bowel lavage solution. Serum concentration and urinary excretion of PEG 4000 were studied in rats and dogs after single or multiple oral administration of MGV-5 at several dosages. Multiple doses of 20 ml (PEG 4000 1.18 g) /kg were given to animals at intervals of 10 minutes.
In rats, serum concentration of PEG 4000 increased with increasing dosages, but the level at 20 ml/kg × 5 doses was similar to that at 20 ml/kg × 10 doses. In dogs, serum concentration of PEG 4000 was not detected at a limit of 10 μg/ml after 1, 4 or 8 doses of 20 m1/kg of MGV-5.
In rats, the urinary excretion % was decreased with increasing dosages, and the percentage was 1.00% at 20 ml/kg × 10 doses. Therefore the same excretion amount of PEG 4000 was found at 20 ml/kg × 5 doses and 20 ml/kg × 10 doses. In dogs, the urinary excretion of PEG 4000 were 0.34, 0.07 and 0.05% at 20 ml/kg × 1, 4 and 8 doses, respectively.
These results suggest the saturation of gastrointestinal absorption of PEG 4000 at both animals.

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The absorption, distribution and excretion of ¹⁴C-labelled propiverine hydrochloride (¹⁴C-P-4) were studied in male and female rats after oral or intravenous (male only) administration of ¹⁴C-P-4 at 1.85 MBq(50μCi)/100 mg/kg (p.o.) and 1.85 MBq(50μCi)/10mg/kg (i.v.).
1. After intravenous administration of ¹⁴C-P-4 to rats, the blood levels of radioactivity decreased biphasically [T_1/2 : 2.0hr(α), 17.2hr(β) ; Vdss : 12.1 L/kg]. After a single oral dose of ¹⁴C-P-4, the time course of the blood radioactivity did not essentially differ between male and female rats [Cmax:4.17 (male), 4.30μg eq./ml(female) ; T_1/2 : 13.5 (male), 10.4hr(female)].
2. After intravenous administration the radioactivity was relatively high in the lung, liver, kidney and muscle. Following oral administration, the radioactivity was relatively high in the liver and kidney while in other tissues was lower than in the blood ; then the radioactivity disappeared gradually from all tissues. Most radioactivity disappeared from each tissue within 72 hr after administration.
3. After intravenous administration rats excreted about 20% of the radioactivity in the urine and about 70% in the feces. Similar excretion pattern was observed after oral administration, where 30-40% and 55-70% of administered dose was excreted to urine and feces, respectively.
4. The bile-duct cannulated rats excreted about 70% of orally administered dose with the bile ; 39% of that amount was reabsorbed. These results suggest the occurrence of enterohepatic circulation.

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Biotransformation of propiverine hydrochloride [1-methyl-4-piperidyl diphenylpropoxyacetate hydrochloride, P-4] was studied in rats after oral administration of P-4.
1. The presence of nine metabolites of P-4 was found in the urine and the bile after oral administration ; they were identified based on a ¹H-NMR and Mass spectra by direct comparison with authentic compounds.
2. Portal plasma concentration of unchanged drug after oral administrati on of ¹⁴C-P-4 was 4 ?? 16 times higher than in peripheral plasma, indicating the presence of the hepatic first pass effect.
3. After oral administration of ¹⁴C-P-4, 1-methyl-4-piperidyl benzilate N-oxide [DPr-P-4 (N → O)] was mainly excreted to the urine, unidentified polar metabolites, benzilic acid [BA], diphenyl-1-(2-hydroxy) propoxyacetic acid [ω-1-OH-Pr-BA], 2, 2-diphenyl-5-methyl-1, 4-dioxan-3-one [ω1-OH-Pr-BA(L)], 1-methyl-4-piperidyl diphenyl-(2-carboxy) ethoxyacetate [ω-COOH-P-4] were excreted to the bile.
4. Conjugates (glucuronide and sulfate) accounting for only 3 ?? 4 % of administered dose were detected in the urine and bile.

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The absorption, distribution, metabolism and excretion of ¹⁴C-labelled propiverine hydrochloride (¹⁴C-P-4) were studied in male rats during and after seven consecutive daily oral administrations of ¹⁴C-P-4 at 100mg/kg. The effect of unlabelled P-4 on the hepatic drug-metabolizing enzymes was examined by a commonly used method in male rats after repeated oral administration.
1. After fifth oral administration of ¹⁴C-P-4 the blood radioactivity reached plateau values. The seventh administration produced a blood level-time curve for radioactivity which was not much different in the elimination phase from that seen after a single administration, however the half life after repeated administration was just a little increased as compared to a single administration.
2. The tissue concentrations during the repeated administration were 1.3 ?? 3 times higher than those observed after a single administration. The tissue level of radioactivity reached a plateau following administration of 4th dose. Radioactive counting and autoradiographic (ARG) experiments did not show any definite accumulation of radioactivity in any particular organ or tissue.
3. Excretion of radioactivity into the urine was almost constant during repeated administration and that into the feces was almost complete within 4 8hr after the final dosing. Similar results were obtained after administration of a single dose. Ninty-nine percent of administered radioactivity was excreted in the urine and feces within 96hr after the final dosing.
4. After repeated oral administration of P-4 to rats its biotransformation was enhanced due to induction of the enzymes involved in N-oxidation and N-demethylation. Therefore we supposed that P-4 was eliminated from plasma or liver fairly soon. And we supposed that due to a slow elimination rate of the polar metabolites (ex. benzilic acid) the total radioactivity after repeated administration was higher than that after single administration.

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The distribution of radioactivity of ¹⁴C-Propiverine hydrochloride (¹⁴C-P-4) in the fetuses and the excretion to the milk was studied following oral administration at a dose of 100mg/kg to pregnant or lactating rats.
1. After oral administration to pregnant rats, a low radioactivity was detected in the fetal tissues. The peak radioactivity in the fetus was 2 times lower when compared to the maternal plasma level and was decreased rapidly.
2. On day 18 of gestation, the ratio of the concentration in the fetal liver to that in its total body was relatively lower, and the distribution to the fetus was not pronounced.
3. Following oral administration of ¹⁴C-P-4 to lactating rats, the radioact ivity transfered into the milk was about 1.2-1.7 times higher than that in maternal plasma. Elimination half-life of the radioactivity from the milk was 13.29 hour. The elimination parameters from the milk were similar to those observed in the plasma.

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It is important to introduce our studies about isoniazid (INH) —induced hepatitis, since INH is widely used as a first line drug for the treatment of tuberculosis all over the world. From a lot of experimental data obtained by us it is clarified that hydrazine (Hz), one of INH metabolites, is a main toxigen of INH-induced hepatitis, and its effective toxins are Hz radical (N H-NH₂) and/or diimide (HN=NH) rather than acetylhydrazine. The radical formed during oxidative metabolism of Hz in rat liver microsomes was spintrapped with α-phenyl-tert-butylnitrone. The trapped species was identified as Hz radical by the examination of its ESR and mass spectra. Further enzymatic experiments provided the evidence, i. e. Hz radical was formed through hydrogen abstraction from Hz by superoxide anion which was released by reduced NADPH cytochrome P-450 (fp₂H₂)-mediated one-electron donation to oxygen molecules. Although rifampicin(RMP)is well-known as an inducer of cytochrome P-450, it was demonstrated by us that the treatment of rats with RMP activated not only INH-amidase but also fp₂ in the liver microsomes of Hz-administered rats. These observations strongly suggest that INHRMP coadministration can accelerate Hz formation from INH initially, following a hydrogen abstraction of Hz to its radical by superoxide anion, and further oxidation of the radical to diimide is increased by cytochrome P-450. These processes might be a key factor of INH-induced hepatitis enhanced by RMP in tuberculous patients on INH-RMP treatment.

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Unusual 1 β-and 6 α-hydroxylated and Δ-unsaturated bile acids were identified from meconium, amniotic fluid and neonatal urine by comparison with the mass spectra of the synthetic standards. In the profile analysis of fetal bile acids, 1 β-hydroxylated cholic acid was predominant in full term amniotic fluid, and neonatal urine, while 6 α-hydroxylated chenodeoxycholic (hyocholic) acid constituted a main component in meconium. Quantity of these bile acids increased according to the progress of gestation and decreased with developmental age after birth. Taurine conjugates are main bile salts in meconium and were exchanged progressively for the glycine conjugates in neonatal biles. These results suggest that hydroxylation at C-1 β or C-6α position and conjugation of bile acids with taurine in fetal liver might be carried out for the elimination of bile acids. Biosynthetic intermediates for the bile acids were synthesized efficiently, and C₂₇-bile acids were determined in the urine of an infant with Zellweger syndrome. There is a review on the fetal bile acid metabolisms and congenital diseases.

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