Biomedical subjects

O Takaiti

Publications and source records attributed to O Takaiti.

At least 19 recordsLinked to original sources

PubMed1995

Metabolism of dopamine prodrug, docarpamine.

Docarpamine is a dopamine prodrug which has been selected from a large number of dopamine derivatives in order to develop an orally effective dopamine. The pharmacokinetics and metabolism after oral administration of docarpamine were studied in rats and dogs. The maximum concentration of free dopamine in plasma after oral administration of docarpamine to rats and dogs was 13 and 4-6 times, respectively, higher than those of dopamine (DA). In the first pass metabolism study in dogs, the main metabolic pathways after oral administration of docarpamine were catechol ester hydrolysis in the small intestine, and amide hydrolysis and conjugation in the liver. Conversion rates from docarpamine to DA in various rat tissue homogenates were in the order of the liver > small intestine > blood. The concentrations of DA conjugate and 3,4-dihydroxyphenylacetic acid in plasma after oral administration of DA to dogs were higher than those of docarpamine. This result indicates that protected groups of the docarpamine molecule suppress the first pass metabolism of orally administered dopamine. In conclusion, the findings of this study suggest that docarpamine can be used as an oral dopamine prodrug. The main first pass metabolism after oral administration of docarpamine are catechol ester hydrolysis in the small intestine, and amide hydrolysis and conjugation in the liver. Free dopamine, which is a pharmacologically active form, is mainly produced in the liver.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Calmodulin antagonistic action of new 1,5-benzothiazepines derived from diltiazem.

A series of newly synthesized 1,5-benzothiazepines derived from diltiazem (CAS 42399-41-7) were tested for calmodulin antagonistic activities using Ca(2+)-calmodulin stimulated phosphodiesterase (PDE). Some compounds possessing the benzoyloxy moieties at position 4 of 1,5-benzothiazepine ring of diltiazem showed a dose-dependent inhibitory action with the potencies comparable to that of a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7). In contrast, diltiazem did not exert the inhibitory action at the same concentrations. Further, radioligand binding experiment, using a radiolabeled 1,5-benzothiazepine, showed that these compounds bound to Ca(2+)-calmodulin complex, but not to calmodulin in the presence of EGTA, suggesting that these 1,5-benzothiazepines are new calmodulin antagonists. Some of these compounds inhibited [3H]diltiazem binding to Ca antagonist binding sites in cell membranes of rat cerebral cortex but with a less potent affinities than diltiazem, suggesting that there was no correlation between their anti-calmodulin effect and the binding affinity to Ca antagonist binding sites. In conclusion, new 1,5-benzothiazepines have been demonstrated to have an anti-calmodulin action. These compounds may possess a pharmacological activity based on their anti-calmodulin action in addition to their interaction with Ca channel.

Animals↗

PubMed1993

Metabolism of clentiazem in rats.

Following oral dosing of [14C]clentiazem to rats the metabolites in urine and bile were separated and their chemical structures were investigated by HPLC and GC-MS analyses. Fifteen basic, 6 acidic, 2 neutral and 4 conjugated metabolites were found in urine and/or bile. Eight basic metabolites (MB1-8) were identified as the synthetic compounds; deacetyl clentiazem (MB1), N-monodemethyl clentiazem (MB2), deacetyl-N-monodemethyl clentiazem (MB3), deacetyl-O-demethyl clentiazem (MB4), N-monodemethyl-O-demethyl clentiazem (MB5), deacetyl-N-monodemethyl-O-demethyl clentiazem (MB6), O-demethyl clentiazem (MB7) and N-didemethyl clentiazem (MB8). The chemical structures of seven basic metabolites (MB9-15) were assigned as follows, deacetyl-N-didemethyl clentiazem (MB9), O-demethyl-N-didemethyl clentiazem (MB10), deacetyl-O-demethyl-N-didemethyl clentiazem (MB11), N-monodemethyl-2-hydroxy-methoxyphenyl clentiazem (MB12), deacetyl-2-hydroxy-methoxyphenyl clentiazem (MB13), deacetyl-N-monodemethyl-2-hydroxy-methoxyphenyl clentiazem (MB14) and deacetyl-N-didemethyl-2-hydroxy-methoxyphenyl clentiazem (MB15). Four acidic metabolites were identified as the synthetic compounds: (+)-(2S,3S)-3-(acetyloxy)-8-chloro-3,4-dihydro-2-(4-methoxyphenyl) -4-oxo-1, 5-benzothiazepin-5(2H)-acetic acid (MA1), deacetyl-MA1 (MA2), O-demethyl-MA1 (MA3) and deacetyl-O-demethyl-MA1 (MA4); and the two remaining acidic metabolites, MA5 and MA6, were presumed to be hydroxylated MA3 and MA4, respectively. Two neutral metabolites were identified as the synthetic compounds; (+)-(2S,3S)-3-(acetyloxy)-8-chloro-3,4-dihydro-2-(4-methoxyphenyl) -4-oxo-1, 5-benzothiazepin-5(2H)-acetonitrile (MN1) and deacetyl MN1 (MN2). Other two metabolites conjugated with glucuronic acid were found in bile and the structures were presumed to be 8-chloro-2,3-dihydro-3-hydroxy-5-(2-hydroxyethyl)-2-(4-hydroxyphenyl)-1, 5-benzothiazepin-4(5H)-one (MN3) and 2-methoxyphenyl MN3 (MN4). The glucuronide or sulfate of MA4 was also detected. These metabolites were formed by a number of pathways including deacetylation, deamination, N-demethylation, O-demethylation, aromatic hydroxylation and conjugation.

Administration, Oral↗

PubMed1993

Disposition and metabolic fate of clentiazem in rats and dogs.

The plasma concentrations and time courses of radioactivity and unchanged drug, the excretion of radioactivity into urine and feces, and the proportion of metabolites in plasma and urine were studied after oral administration of [14C]clentiazem to male and female rats and dogs. Apparent sex-related differences were found in the disposition and metabolism of clentiazem in rats. The plasma levels of radioactivity and acidic metabolites were higher in males than in females. The plasma levels of unchanged drug, on the other hand, were about the same in both sexes. Higher conversion of clentiazem to its acidic metabolites in the liver of male rats and higher excretion of the acidic metabolites in the urine of female rats, presumably due to sex-related differences in cytochrome P-450 and renal clearance, respectively, seem to explain these differences in the disposition of clentiazem in male and female rats. No suggestion of a similar sex difference was found in dogs. The plasma concentrations and time courses of radioactivity and unchanged drug in male dogs were similar to those in female dogs, and the excretion of radioactivity in both sexes was also similar. The main plasma metabolite in male and female dogs was O-demethyl clentiazem (MB7). A species difference between rat and dog was suggested, since the major metabolic pathways were different and no sex difference was found in dogs.

Animals↗

PubMed1993

Effects of the new anti-ulcer drug ecabet sodium (TA-2711) on pepsin activity. I. Inactivation of enzyme protein.

To investigate the mechanism of the anti-peptic action of ecabet sodium (TA-2711) observed in pylorous-ligated rats, effects of this drug on the peptic activity of rat gastric juice, purified hog pepsin and pepsinogen were studied in vitro. After incubation with or without ecabet at acidic pH, the reaction mixture was centrifuged, and the peptic activity of the supernatant was measured. Ecabet depressed the peptic activity of pepsin and pepsinogen in parallel with a decrease in the protein concentration of the respective supernatant. Depression was greatest with pepsinogen (97% at 2.5 mg/ml of the drug) followed by gastric juice (about 60% at 10 mg/ml), and inhibition of the peptic activity of pepsin was weakest (about 10% at 10 mg/ml). When a fraction of the rat gastric juice containing substances with molecular weights below 10,000 was added to the pepsin solution, the anti-peptic activity of ecabet was potentiated. These results suggest that oral dosing of ecabet reduces the peptic activity of gastric juice by precipitating pepsin, which is facilitated by an unknown component(s) of gastric juice, and that the inactivation of pepsinogen may also contribute to the anti-peptic activity of ecabet.

Abietanes↗

PubMed1993

Effects of the new anti-ulcer drug ecabet sodium (TA-2711) on pepsin activity. II. Interaction with substrate protein.

To define the mechanism of the protection by ecabet (TA-2711) of the gastric mucosa from peptic attack, the characteristics of protein binding of this drug and its effect on peptic hydrolysis of substrate proteins were investigated in vitro. Both the binding to proteins and the hydrophobicity of ecabet were dependent on the pH; the lower the pH, the higher both parameters. The percentage of ecabet bound to proteins was nearly constant, being independent of the drug concentration at pH's below 2, indicating that this drug is bound to proteins in a non-specific manner. The activity of peptic hydrolysis of bovine serum albumin (BSA) decreased in the presence of ecabet, and this was not due to the interaction between pepsin and ecabet judging from the kinetic studies. The apparent Km values of peptic hydrolysis of BSA increased depending on the quantity of ecabet bound to BSA. These results suggest that ecabet is bound to substrate proteins by a non-specific hydrophobic interaction to form a complex that is less vulnerable to peptic hydrolysis.

Abietanes↗

PubMed1992

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)

Administration, Oral↗

PubMed1992

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)

Administration, Oral↗

PubMed1992

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)

Administration, Oral↗

PubMed1992

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.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 5th communication: isolation and identification of metabolites of imidapril in rats, dogs, and monkeys.

The metabolism 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) was studied in rats and dogs after oral or intravenous administration of [N-methyl-14C]-imidapril or [alanine-3-14C]-imidapril, and in monkeys after oral administration of [alanine-3-14C]-imidapril. Radio-chromatographic analysis of the metabolites of imidapril from the plasma, urine, and bile of rats, dogs, or monkeys resulted in the detection of at least four metabolites. These four metabolites were isolated and characterized by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry(GC-MS). Of these metabolites, M1 (6366 A, CAS 89371-44-8) was pharmacologically active; however, M2, M3, and M4 were inactive. There was no evidence of any glucuronides or sulfates of drug-related compounds, or of the piperazine-dione lactam type metabolites of imidapril or 6366 A in the urine of the animals used. Imidapril was metabolized by hydrolysis at the carboxylic ethyl ester side-chain to give M1, and by cleavage of the amide bond to form M2 and M3. M4 was formed by hydrolysis of M3 and/or cleavage of the amide bond of M1. Qualitatively, the same metabolites were found in all animal species tested; however, quantitatively, there were differences in the amounts of metabolites formed depending on the species.

Administration, Oral↗

PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 6th communication: interspecies comparison of pharmacokinetics and excretion of imidapril metabolites in rats, dogs, and monkeys.

The pharmacokinetics and excretion of the main metabolites 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 investigated in rats, dogs, and monkeys after oral or intravenous administration of [N-methyl-14C]-imidapril and [alanine-3-14C]-imidapril. After oral administration of 14C-labeled imidapril to rats and dogs, the plasma concentrations of the pharmacologically active metabolite, 6366 A (M1, CAS 89371-44-8), reached a peak at 1-2 h in rats and at 2-6 h in dogs. The disappearance half-lives of M1 from plasma were much longer in dogs (6.3-9.3 h) than in rats (0.9-2.3 h). At the point of peak plasma radioactivity, the major radioactive metabolites in the plasma were M2, followed by M3, M4 greater than M1 in rats; in dogs, M2 and M3 followed by M1 greater than M4. After intravenous administration of [N-methyl-14C]-imidapril to rats and dogs, plasma levels of M1 reached a peak at the first measuring time of 5 min in rats and at about 2 h in dogs. The half-lives of plasma M1 levels were similar to those after oral dosing. At 1 h after dosing, the major metabolites in plasma were M1 followed by M2 in both rats and dogs. Irrespective of the route of administration, unchanged imidapril disappeared more rapidly from the plasma in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1992

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)

Adult↗

PubMed1991

Binding characteristics of a new 1,5-benzothiazepine, clentiazem, to rat cerebral cortex and skeletal muscle membranes.

The binding properties of a new 1,5-benzothiazepine, clentiazem (TA-3090), were investigated in rat cerebral cortex and skeletal muscle membranes with [3H]diltiazem and [3H]nitrendipine as radioligands. Clentiazem inhibited [3H]diltiazem binding to cerebral cortex membranes at the same concentrations as diltiazem at 2 degrees C. However, at 37 degrees C clentiazem was 3 times more potent to inhibit binding than diltiazem. [3H]Nitrendipine binding was modulated by clentiazem in a temperature-dependent manner. At 37 degrees C clentiazem significantly enhanced [3H]nitrendipine binding to rat cerebral cortex membranes, whereas it has an inhibitory effect on [3H]nitrendipine binding at 0 degree C and no effect at 25 degrees C. Of two optical isomers of clentiazem and four of diltiazem, only d-cis isomers (clentiazem and diltiazem) increased [3H]nitrendipine binding, indicating that both compounds have the same stereoselectivity for increasing [3H]nitrendipine binding. These results suggest that clentiazem binds to the same 1,5-benzothiazepine binding sites as diltiazem but with greater affinity.

Animals↗

PubMed1991

Metabolic fate of a new anti-ulcer drug (+)-(1R,4aS,10aR)- 1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1- methylethyl)-6-sulfo-1-phenanthrenecarboxylic acid 6-sodium salt pentahydrate (TA-2711). I. Disposition, metabolism and protein binding in rats and dogs.

Metabolic fate of (+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a-octahydro-1,4a- dimethyl-7-(1-methyl-ethyl)-6-sulfo-1-phenanthrenecarboxylic acid 6-sodium salt pentahydrate (TA-2711), a new anti-ulcer drug, was studied in animals using 14C-TA-2711. The absorption was estimated to be 3.4-7.0% of dose in rats. The plasma radioactivity after oral dosing peaked at 5-6 h in rats and at 2 h in dogs, and their elimination half lives (beta) were about 120-130 h. After oral or intravenous administration of TA-2711 to rats, the concentrations of radioactivity in most of the tissues were much lower than that in the plasma, indicating the low transfer of TA-2711 into the tissues from the plasma. In whole body autoradiograms of rats, most of the radioactivity given orally was localized in the gastrointestinal tract. Almost all the radioactivity given orally was excreted to the feces while the urinary excretion was extremely low. The sole and slight metabolite, glucuronide of TA-2711, was detected only in the urine of rats and dogs after oral dosing. During the consecutive oral dosing once a day for 21 d to rats, the plasma levels attained the steady state after administration of drug 7-10 more times. After the final dosing, the patterns of disappearance of radioactivity in the plasma were similar to those in the tissues, and the tissue/plasma ratios of the concentrations were similar to those after single dosing, suggesting no accumulation in rat tissues. More than 96% and about 85% of TA-2711 was bound in vitro to human and rat serum proteins, mainly albumin, respectively. No radioactivity was found in fetus and milk of rats given oral administration.

Abietanes↗

PubMed1991

Metabolic fate of a new anti-ulcer drug (+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a- octahydro-1,4a-dimethyl-7-(1-methylethyl)-6-sulfo-1- phenanthrenecarboxylic acid 6-sodium salt pentahydrate (TA-2711). II. Distribution in the rat stomach.

The distribution of (+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a-octahydro-1,4a- dimethyl-7-(1-methylethyl)-6-sulfo-1-phenanthrenecarboxylic acid 6-sodium salt pentahydrate (TA-2711) in stomach was studied after oral administration of 14C-TA-2711 (100 mg/kg) to rats. At 6 h after dosing, most of the radioactivity was found in the lower intestine, caecum and large intestine. However, the radioactivity in the stomach was higher than that in the upper and middle small intestine. The concentration of the radioactivity in the glandular stomach was about 1.5 mg eq. TA-2711/g at 30 min after administration. Thereafter, it decreased gradually to about 60 micrograms eq. TA-2711/g at 6 h after dosing. In the radioluminograms of 6 and 24 h after dosing, most of the radioactivity was observed on the surface of gastric mucosa. After administration to rats with gastric ulcer induced by acetic acid, higher radioactivity was observed in the ulcerated tissues of the stomach than in the nonulcerated control tissues. In the stomach damaged by ethanol, the concentrations of radioactivity in lesion parts were also higher than those in non-lesion parts. In the microautoradiograms of gastric mucosa damaged by ethanol, the developed silver grains were densely distributed in necrotic tissues.

Abietanes↗

PubMed1990

A new method for the high performance liquid chromatographic determination of TA-870, a dopamine prodrug (catechol ester compound).

A new method for the high performance liquid chromatographic (HPLC) determination of N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870), a dopamine prodrug, in biological fluid has been developed. In order to measure with an electrochemical detector (ECD), TA-870 was passed first through an immobilized carboxylesterase column to be converted to the electrochemically active deethoxycarbonylated TA-870 (DEC-TA-870). The properties of this carboxylesterase immobilized on Sepharose 4B were examined by this flow injection system. Hydrolysis of TA-870 with this immobilized carboxylesterase was a maximum at pH 7-8 and 50 degrees C, and the activity decreased in the presence of organic solvent such as acetonitrile. For the determination of TA-870 in biological fluids, an HPLC-immobilized enzyme-ECD system using a column-switching technique was developed. The blood was deproteinized with ethanol, and TA-870 in the ethanol extracts was adsorbed in Bond Elut C18. The dichloromethane eluate from Bond Elut C18 was injected into the HPLC system. The HPLC apparatus was composed of three pumps, two separation columns (LiChrosorb Si 60 and mu Bondasphere), a trap column (Bond Elut), an enzyme column, ECD and the column-switching system. The calibration curve for TA-870 in blood was linear in the range from 2 to 200 ng/mL. This new assay method might be useful also for the determination of other catechol ester compounds.

Animals↗

PubMed1990

Metabolism of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and dopamine after oral administration to rats and dogs.

The metabolism of an orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and of dopamine (DA), were studied by use of thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) for identification and analysis of urinary and biliary metabolites after p.o. and/or i.v. administration to rats and dogs. The conjugated/free ratios of the metabolites were also determined. The urinary metabolites and order of the excretion in rats after p.o. dosing of TA-870 (30 mg/kg) were DA greater than homovanillic acid (HVA) greater than 3,4-dihydroxyphenylacetic acid (DOPAC) greater than 3-hydroxyphenylacetic acid (3-HPAC). Those in dogs (33.5 mg/kg p.o.) were DA greater than HVA greater than de-ethoxycarbonylated TA-870 (DEC-TA-870) not equal to DOPAC. The urinary metabolites and order of the excretion in rats after p.o. dosing of DA (12 mg/kg, equimolar dose to TA-870) were DA greater than DOPAC greater than HVA greater than 3-HPAC, while those in dogs (13.5 mg/kg) were DOPAC greater than DA greater than HVA. The composition of the main urinary metabolites of TA-870 are similar in rats and dogs but after p.o. dosing of DA, excretion of DOPAC in dogs is much (ca. 3 times) higher than that in rats. After administration of DA and TA-870, 3-HPAC was found as a novel metabolite of DA, which was thought to be formed by dehydroxylation of DOPAC or DA with intestinal flora.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗