Metabolic fate of the new anti-ulcer drug enprostil in animals. 2nd communication: whole-body autoradiographic distribution of [3H]-enprostil in rats

The distribution of radioactivity was studied by whole-body autoradiography in rats after oral or intravenous administration of [3H]-enprostil ((+/-)-11a-15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorp r osta-4,5,13(t)- trienoic acid methyl ester, TA-84135) at a dose of 23 micrograms/kg. After oral administration to male rats, radioactivity in almost all the tissues and organs reached a peak within 15 min to 1 h. The highest levels of radioactivity were found in the contents of the stomach and intestine. High levels of radioactivity were also observed in the liver and kidney, and moderate levels were found in the lung, blood, dental pulp and the walls of the stomach. Radioactivity was the lowest in the skeletal muscle, testis, eye and brain. After reaching peak levels, radioactivity in the body decreased gradually, and it was detected only in the excretory organs at 24 h after drug administration. The distribution pattern after the intravenous dose was essentially similar to that after oral administration. The distribution profile of radioactivity in non-pregnant female rats after an oral dose was similar to that in male rats. Placental transfer and excretion in milk of radioactivity was slight. When the affinity of this compound to the melanin-containing tissues such as the uveal tract of the eye and the hair follicle was examined using pigmented rats, no tendency to retention of radioactivity in these tissues was observed.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 3rd communication: tissue accumulation after consecutive oral administration of [N-methyl-14C]-imidapril in rats.

Accumulation characteristics of radioactivity in the organs and tissues, metabolism, and excretion of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), an oral angiotensin-converting enzyme inhibitor, were investigated after consecutive oral administration of [N-methyl-14C]-imidapril at a once-daily dose of 1 mg/kg to male rats for 14 days. During the consecutive oral administration, the plasma radioactivity levels at 1 h after each dose reached steady-state following the 3rd to 4th administered dose; this was about 1.4 times higher than the corresponding plasma levels of the first dose. At 24 h after each administration, the plasma levels attained a steady-state at 3-4 days after the beginning of the consecutive dosing. Examination of the time course of plasma radioactivity after the single and multiple (7 and 14 times) oral administration revealed that the Cmax and AUCO-24 h values slightly, but significantly, increased according to repeated dosing and the beta-phase of the t1/2 of disappearance became longer after consecutive dosing. However, these values were not markedly different among consecutive dosing groups. The extent and rate of excretion of radioactivity in the urine and feces were nearly constant during the periods of consecutive oral administration, and were also similar to those after the single oral administration. Total recovery of radioactivity from urine and feces within 96 h after the final dosing was more than 98% of the total dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 4th communication: effect on hepatic drug metabolizing enzyme system in rats

Effects of multiple oral administration of enprostil ((+/-)-11 alpha,15 alpha-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorprosta- 4,5,13(t)-trienoic acid methyl ester, TA 84135) (20 micrograms/kg/d) and its solvent propylene carbonate (PC, 100 microliters/kg/d) on body weight gain, liver weight, hepatic drug metabolizing enzyme system and hexobarbital sleeping time were investigated in male rats during a 14-day period. Cytochrome P-450 content (as compared to the untreated control) and cytochrome b5 content (as compared to PC treated group) were slightly, but significantly, reduced in the group given a single oral dose of enprostil. However, these slight reductions were not augmented significantly by repeated administrations of enprostil. Slight but significant increase in microsomal protein content was observed in the group given 14 oral doses of enprostil and PC. Enprostil did not affect the other indicators used to evaluate the status of the hepatic drug metabolizing enzyme system. Additionally, single or multiple oral doses of enprostil or PC showed no effect on the hexobarbital-induced sleeping time. It therefore may be safely concluded that multiple oral administration, both of enprostil and of PC, has very little effect on drug metabolizing enzyme inducing or inhibiting activity in rats.     

Metabolic fate of the new cardiotonic denopamine in animals. 2nd communication: tissue accumulation in the rat after consecutive oral administration of 14C-denopamine

Accumulation characteristics of (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (denopamine, TA-064) in organs and tissues were investigated after oral administration of 14C-denopamine to rats once a day (5 mg/kg/d) for 1, 6 and 10 days. The levels of radioactivity in each organ and tissue were measured at various time intervals after the final dose. The levels of radioactivity at 15 min after administration were generally higher in the consecutive-dose groups than in the single-dose group. However, the levels were equilibrated within 6 days of administration. Radioactivity at 24 h after administration decreased to about the detection limit in each group. In addition, half-lives of disappearance of radioactivity from the body were not significantly affected by the consecutive doses. About 100% of the dose was recovered from the urine and feces during consecutive administration periods. Consequently, it was considered that the drug hardly showed retention and accumulation characteristics in the body.     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 1st communication: absorption, distribution and excretion in the mouse, rat and rabbit

Absorption, distribution and excretion of [3H]-enprostil ((+-)-11a,15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorpr osta -4,5,13(t)-trienoic acid methyl ester, TA-84135), a new anti-ulcer prostaglandin, were studied in mice, rats and rabbits. Radioactivity associated with enprostil was rapidly absorbed from the gastrointestinal tract with Tmax values of 15 or 30 min. Absorption was also efficient inasmuch as approximately 80% of an oral dose was recovered in bile and urine in 24 h in bile duct-cannulated rats. Experiments in pylorus-ligated, bile duct-cannulated rats demonstrated that enprostil was mainly absorbed from the intestine, rather than from the stomach. In mice given oral doses of 2, 8 and 32 micrograms/kg, Cmax and AUC values of enprostil radioequivalents increased proportionately to the increase in dose, indicating linear kinetics over this dose range. Distribution of enprostil-associated radioactivity was investigated in rats by quantitating tritium in various tissues after the oral administration of [3H]-enprostil. Radioactivity in tissues was highest at 15 or 30 min after dosing. Highest levels of radioactivity were found in the stomach and intestines, the organs which came into direct contact with the dose, and the liver and kidney, the organs involved in excretion of enprostil. The rate of elimination of enprostil-associated radioactivity from all tissues and from plasma was similar. Enprostil-associated radioactivity did not accumulate in any tissue. Radioactivity was found in fetuses following oral administration of [3H]-enprostil to rats on the 12th or 19th day of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The absorption of [G-3H]-acetylglycyrrhetate after oral administration to rats.

A tritium-labelled form of aluminium acetylglycyrrhetate has been synthesised by catalytic exchange with tritiated water. An oral dose of aluminium [3H]-acetylglycyrrhetate to rats was mainly excreted in the faeces (a mean of 73%). A mean of 4% was excreted in the urine and after five days 17% of the radioactivity was retained in the carcass. The amounts of non-volatile (drug-related radioactivity excreted in faeces and urine during five days were 65% and 3%, respectively, while 6% was retained in the carcass. The total amount of tritiated water produced was 24% of the dose. Experiments in rats with cannulated bile ducts indicated that much of the faecal radioactivity represented unabsorbed drug. 15% of an oral dose was eliminated in bile during 2 days. A minimum value for the extent of absorption of an oral dose was estimated as 21%. Plasma levels of radioactivity were very low and peak levels of drug-related radioactivity were reached at 30 min and represented about 0.2% of the dose in total plasma.     

Excretion of [3H]triptolide and its metabolites in rats after oral administration

Aim： To investigate the routes of elimination and excretion for triptolide recovered in rats.
Methods： After a single oral administration of [3H]triptolide （0.8 mg/kg, 100 μCi/kg） in Sprague Dawley rats, urine and fecal samples were collected for 168 h. To study biliary excretion, bile samples were collected for 24 h through bile duct cannulation. Radioactivity was measured using a liquid scintillation analyzer, and excretion pathway analysis was performed using an HPLC/on-line radioactivity detector.

Results： The total radioactivity recovered from the urine and feces of rats without bile duct ligation ranged from 86.6%–89.1%. Most of the radioactivity （68.6%–72.0%） was recovered in the feces within 72 h after oral administration, while the radioactivity recovered in the urine and bile was 17.1%–18.0% and 39.0%–39.4%, respectively. The HPLC/on-line radiochromatographic analysis revealed that most of the drug-related radioactivity was in the form of metabolites. In addition, significant gender differences in the quantity of these metabolites were found： monohydroxytriptolide sulfates were the major metabolites detected in the urine, feces, and bile of female rats, while only traces of these metabolites were found in male rats.

Conclusion： Radiolabeled triptolide is mainly secreted in bile and eliminated in feces. The absorbed radioactivity is primarily eliminated in the form of metabolites, and significant gender differences are observed in the quantity of recovered metabolites, which are likely caused by the gender-specific expression of sulfotransferases.     

Metabolic fate of the new cardiotonic denopamine in animals. 3rd communication: placental transfer and excretion into milk in the rat

3H-labelled (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (denopamine, TA-064) was administered orally to pregnant rats at a dose of 5 or 60 mg/kg on the 14th or 20th day of pregnancy. Irrespective of the doses and the stages of pregnancy, radioactivity in the fetus reached a peak at 30 min after administration, being 1/7 to 1/25 of the maternal plasma levels. Total radioactivity in each fetus at 30 min was estimated to be only about 0.002 to 0.06% of the dose. Disappearance of radioactivity from the fetus, uterus and amniotic fluid was slightly slower than that from the maternal plasma. After 3H-denopamine (5 mg/kg) was orally administered to lactating rats on the 12th day after delivery, radioactivity in milk was generally lower than in the blood of the dams, and time to the peak levels in milk tended to delay as compared with that in the blood. The levels of radioactivity in the blood of the sucklings, nursed by their dams, at 1 h after nursing were about 1/30 of the maternal blood levels, showing a slight transfer of the drug and/or its metabolites via milk. At 24 h after administration, radioactivity levels in the sucklings decreased to near the detection limit. The results of whole body autoradiography were generally consistent with the quantitative data on the placental transfer and excretion into milk.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 2nd communication: tissue distribution and whole-body autoradiography of imidapril in rats.

Tissue distribution, whole-body autoradiography and metabolic profiles in selected tissues of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) were studied in male and female rats after oral and intravenous administration of [N-methyl-14C]-imidapril (1 and 5 mg/kg) or [alanine-3-14C]-imidapril (1 mg/kg). After oral administration of [N-methyl-14C]-imidapril, radioactivity was distributed relatively rapidly to all tissues, except for the central nervous system. Maximum concentrations in most tissues were observed at 30 min to 1 h after dosing. Concentrations greater than those in the plasma were found in the liver, kidney and particularly in the lung except for the gastrointestinal contents. The elimination from the lung was relatively slow (t1/2: ca. 28 h). At 96 h after dosing, there was no evidence of remaining radioactivity in any tissues, except for the lung and kidney. No gender-related differences in the tissue distribution profile of radioactivity were observed in the whole-body autoradiogram. After intravenous administration, the distribution pattern of radioactivity was similar to the results of oral administration, except for the gastrointestinal contents. There was no specific binding of drug-related compounds to melanin-containing tissues such as the hair follicles and the uveal tract of the eye in the pigmented rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the metabolic fate of 14C-rokitamycin. II. Accumulation of radioactivity in rats after consecutive oral administration

After a consecutive oral administration of 200 mg/kg/day of 14C-rokitamycin (TMS-19-Q) daily for 28 days to male rats, the accumulation of radioactivity in tissues and its disappearance after the cessation of the administration was studied. Blood concentrations at peak times and 24 hours after each administration were determined daily. Both values increased gradually until the 14th day and thereafter remained roughly constant. The extent of elimination of radioactivity from the blood was practically not affected by the consecutive administration. Affinities of radioactivity to the liver, kidney, spleen, adrenal, pituitary gland, preputial gland, thyroid, intraorbital lacrimal gland and bone marrow were comparatively higher than those to other tissues. Tissue concentrations in the above mentioned tissues at the 1st day after the completion of consecutive administrations for 14 and 28 days were 2.6-6.1 and 3.2-6.8 times higher, respectively, than those at the 1st day after a single administration. The elimination of radioactivity from the tissue after the consecutive administration for 28 days was slightly slower than that after a single administration. In the consecutive daily administration for 28 days, the metabolic fate of radioactivity reached a steady state after 14 days of consecutive daily administration. Hence, the accumulation of the radioactivity did not particularly occurred. During the consecutive administration, recoveries of radioactivity in the urine and feces were almost at a constant rates, with 8.0 and 93.8% of the total radioactivity given excreted in the urine and feces, respectively, within 10 days after the last administration.     

Metabolic fate of delmopinol in man after mouth rinsing and after oral administration

1. The metabolism of delmopinol, an inhibitor of plaque formation and gingivitis. has been studied after mouth rinsing or an oral dose of 14C-delmopinol to healthy male volunteers. The metabolite pattern was studied in urine and plasma samples (unhydrolysed or hydrolysed with conjugate cleaving enzymes) by liquid chromatography (LC) with radio detection. Metabolite identifications were carried out by gas chromatography-electron-impact mass spectrometry (GC-MS) and by liquid chromatography-thermospray mass spectrometry (LC-MS). 2. The metabolic clearance of delmopinol was high, and < 0.2% of the dose was excreted as intact delmopinol in the urine. The main metabolites were, for both administration routes, glucuronide conjugates of delmopinol and of (omega-1-hydroxy) delmopinol. These metabolites were predominant and accounted for nearly the entire urinary radioactivity and most of the plasma radioactivity. After mouth rinsing, parent delmopinol was also one of the main compounds in plasma. 3. Several other products of oxidation of the aliphatic side-chain were present in minor amounts in urine. These metabolites also appeared to be excreted as glucuronic acid conjugates. 4. Glucuronidated (omega-1-hydroxy) delmopinol separated into three peaks by the LC system used. This could be due to different chromatographic properties of conjugate isomers, positional or optical.     

Metabolic fate of delmopinol in man after mouth rinsing and after oral administration

1. The metabolism of delmopinol, an inhibitor of plaque formation and gingivitis, has been studied after mouth rinsing or an oral dose of ¹⁴C-delmopinol to healthy male volunteers. The metabolite pattern was studied in urine and plasma samples (unhydrolysed or hydrolysed with conjugate cleaving enzymes) by liquid chromatography (LC) with radio detection. Metabolite identifications were carried out by gas chromatography-electron-impact mass spectrometry (GC-MS) and by liquid chromatography-thermospray mass spectrometry (LC-MS). 2. The metabolic clearance of delmopinol was high, and &lt; 0.2% of the dose was excreted as intact delmopinol in the urine. The main metabolites were, for both administration routes, glucuronide conjugates of delmopinol and of (ω-1-hydroxy) delmopinol. These metabolites were predominant and accounted for nearly the entire urinary radioactivity and most of the plasma radioactivity. After mouth rinsing, parent delmopinol was also one of the main compounds in plasma. 3. Several other products of oxidation of the aliphatic side-chain were present in minor amounts in urine. These metabolites also appeared to be excreted as glucuronic acid conjugates. 4. Glucuronidated (ω-1-hydroxy) delmopinol separated into three peaks by the LC system used. This could be due to different chromatographic properties of conjugate isomers, positional or optical.     

Pharmacokinetics of the new antihypertensive agent nipradilol in rats. 1st communication: Metabolism and disposition after single oral administration of [14C]nipradilol

The metabolism and disposition of a new antihypertensive and antianginal agent, 3,4-dihydro-8-(2-hydroxy-3-isopropylamino)propoxy- 3-nitroxy-2H-1-benzopyran (nipradilol, K-351) were studied using its [14C]-labelled compound in rats. The plasma level of radioactivity reached the maximum 1 h after oral administration, and the majority of radioactivities administered were recovered in urine and via the bile in feces within 48 h. From the foregoing it is obvious that the drug was absorbed from the gastrointestinal tract rapidly and well, and was eliminated from the body completely. The unchanged drug detected in the plasma and urine after oral administration of 30 mg/kg was more than 10 times as much as that after 3 mg/kg. This fact indicates that the first-pass metabolism of the drug has been saturated. Denitronipradilol, 4- and 5-hydroxynipradilol, and 4- and 5-hydroxydenitronipradilol were identified as major metabolites in the plasma and excreta, and the degradation compounds of the aminohydroxypropoxy side chain were also found as minor metabolites. Among these metabolites, 4-hydroxy metabolites were found mainly as unconjugates and 5-hydroxy metabolites as glucuronides, respectively. These findings suggest that the possible metabolic pathways of nipradilol in rats involve reductive denitration of the nitroxy group, hydroxylation at the benzopyran skeleton, oxidative degradation of the beta-blocking side chain and their glucuronidation.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 4th communication: placental transfer and secretion into milk in rats.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylproply]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-car box ylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) labeled with 14C was administered orally or intravenously to pregnant rats on the 13th or 19th day of pregnancy, and lactating rats on the 7th or 13th day after delivery at a dose of 1 or 5 mg/kg. The placental transfer and the secretion into milk were studied using whole-body autoradiographic methods and/or quantitative determination of total radioactivity after autopsy. Irrespective of the stages of pregnancy, the placental transfer of imidapril was low in the rats after oral administration. The transfer of total radioactivity per fetus on the 13th and 19th day of pregnancy was below 0.001 and 0.07%, respectively, of the dose to their dams during the observation periods. This indicates that the substance-associated radioactivity penetrates the placental barrier to a low extent. After oral administration of [N-methyl-14C]-imidapril to lactating rats on the 7th day after delivery, the concentration of radioactivity in the milk attained a peak at 4 h after administration (0.05 microgram equivalents of imidapril/g), which was about 1/3 of Cmax in the blood. The transfer of imidapril and/or its radioactive metabolites to each suckling via milk after oral dosing was only below 0.03% of the dose to the dams on the 13th day after delivery during the observation periods. The present autoradiographic findings confirmed the above results of tissue distribution studies.     

Metabolic fate of 1-hexylcarbamoyl-5-fluorouracil after oral administration in mice

1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro[6-14C]uracil (¹⁴C-HCFU) was compared with that of 5-fluoro[6-14C]uracil (¹⁴C-FU) after oral administration to mice.

2. 1-(5-Hydroxyhexylcarbamoyl)-5-fluorouracil (5-hydroxy-HCFU) and 1-(5-oxohexylcarbamoyl)-5-fluorouracil (5-keto-HCFU) were found as major intermediate metabolites of ¹⁴C-HCFU and were produced by ω-1 oxidation.

3. FU was detected in plasma 180min after oral administration of ¹⁴C-HCFU, whereas unchanged FU disappeared within 60min after ¹⁴C-FU.

4. ¹⁴C-HCFU and resulting FU were retained in tissues for a long period after oral administration, while administered ¹⁴C-FU was rapidly degraded.     

Deposition of [3H]cocaine, [3H]nicotine, and [3H]flunitrazepam in mouse hair melanosomes after systemic administration.

Microautoradiography was employed to show that association of drugs from the serum directly with forming hair pigment is a primary pathway of deposition into the hair. After systemic administration of [3H]flunitrazepam, [3H]nicotine, and [3H]cocaine, association of all three drugs with melanin in the forming hair was observed within minutes of dosage. Sebum was determined to be an insignificant deposition route for all three drugs. Pigmented mice had significantly higher concentrations of all three drugs than did nonpigmented mice. The results provide a better basis for ultimately using hair for reliable analysis of drug and environmental toxin exposure.     

氚标记盐酸川丁特罗的合成和大鼠口服后排泄动力学（英文）

目的探讨大鼠口服放射性氚标记盐酸川丁特罗([3H]SPFF)后经尿、粪和胆汁的排泄动力学特征。方法采用化学法合成[3H]SPFF,并进行放化纯度鉴定。粪尿排泄实验观察SD大鼠经口45.5 MBq·kg-1(1 mg·kg-1)给药后168 h内经尿和粪累积放射性排出率。胆汁排泄实验观察胆汁引流模型大鼠给药后,72 h内胆汁累积放射性排出率。HPLC-放射性检测法鉴定单只大鼠尿和胆汁中放射性成分组成。结果化学法合成获得5 m L[3H]SPFF甲醇溶液(比活度403 GBq·g-1),化学纯度>96%,放化纯>97%。粪尿排泄实验的结果表明,经口给药后,SD大鼠体内放射性物质经泌尿系统排出较快,168 h经尿粪累积排出率达84.74%,其中尿回收56.63%,粪回收28.10%。胆汁排泄实验显示,给药后3 d,经胆汁放射性累积排出率为29.3%。放射性组成分析结果显示,单只SD大鼠给药后72 h尿液中累积总放射性排出量占给药量的48.61%,其中原型占4.71%,产物占42.62%。72 h胆汁中累积总放射性排出量占给药量的28.14%,其中原型占9.51%,产物占18.63%。结论大鼠经口盐酸川丁特罗后吸收完全,主要经尿液以代谢物形式排泄。     

Disposition of [3H]cloflumide, a new neuroleptic drug, in rats

The disposition of cloflumide (VUFB 15496), 2-chloro-7-fluoro-10 [4-(carbamoylethyl)piperazino]-10,11-dihydrodibenzo [b,f] thiepin methansulfonate, a new neuroleptic agent, following single oral and intravenous dose was studied in the rat using radiotracer techniques. [3H]Cloflumide was almost completely absorbed from the gastrointestinal tract; peak plasma levels of the parent drug were attained within 4 h of oral drug administration. The mean residence time of the unchanged drug was 2.75 h after intravenous administration. The total neuroleptic activity in plasma determined by radioreceptor assay paralleled with plasma cloflumide level indicating that the dopamine inhibiting action is mediated solely by the parent drug. Concentration of radioactive substances was high in the liver and kidneys; in the brain was slightly higher than blood level. Total radioactive meterial as well as unchanged cloflumide were mostly excreted in feces (87 and 10%, respectively). At 3 days postdosing, 96% of the administered dose was recovered.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 7th communication: in vitro metabolism.

In order to clarify the sites of metabolism and the metabolizing enzymes of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1- ethoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), metabolism studies were carried out using rat, dog, monkey, and human plasma and rat tissue homogenates. After incubating with the various plasma samples, imidapril was mainly metabolized to the pharmacologically active metabolite, 6366 A (M1, CAS 89371-44-8), in rat plasma; on the other hand, the ester bond of imidapril was not hydrolyzed in dog, monkey, and human plasma. Imidapril was metabolized to M1, M2, M3, and M4 in all rat tissue homogenates tested. Aside from the above metabolites, no other metabolites were detected. The metabolic activity of imidapril to M1 was the highest in the liver, followed by the kidney and lung; however, it was low in other tissue homogenates. From the results of experiments using certain esterase inhibitors, it has been concluded that the metabolic conversion of imidapril to M1 is mainly due to a carboxylesterase (B-esterase). In contrast, the metabolic activity of imidapril to M2 and M3 (or M4) was highest in the kidney and small intestine while low in other tissues. From the experiments using certain enzyme inhibitors, it has been found that an acetylesterase (C-esterase) is largely involved in the metabolism of imidapril into M2 and M3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 1st communication: absorption, pharmacokinetics and excretion in rats and dogs.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) is an ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, 6366 A (CAS 89371-44-8). Absorption, pharmacokinetics and excretion of imidapril were studied in rats and dogs after oral and intravenous administration of [N-methyl-14C]-imidapril and [N-methyl-14C]-6366 A (1 mg/kg). Following oral administration of 14C-labeled imidapril and 6366 A to rats, plasma concentrations of radioactivity were much higher after [N-methyl-14C]-imidapril dosing than after [N-methyl-14C]-6366 A dosing at all time points. Imidapril was relatively rapidly absorbed from the digestive tract and easily metabolized to the pharmacologically active 6366 A after oral dosing in the rats and dogs. Thus, imidapril proved to be an orally usable 6366 A prodrug. More than 62% and 38% of the dose were assumed to be absorbed from the gastrointestinal tract in the rats and dogs, respectively. The in situ absorption study showed that [N-methyl-14C]-imidapril was absorbed from nearly the entire rat small intestine, especially from the jejunum, but hardly absorbed from the stomach. After oral administration, peak levels of radioactivity in the plasma occurred at 1 h in rats and 30 min to 2 h in dogs. The disappearance of unchanged drug from the plasma was much faster in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)