Metabolism of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The metabolic profiles of nilvadipine in the excreta of male rats and dogs were studied after i.v. and oral dosing. Six types of metabolites were isolated and identified from the urine of male rats and dogs or bile of rats.

2. Several metabolites were detected in the urine (12) and bile (17) of rats by two-dimensional t.l.c., after dosing with ¹⁴C-nilvadipine. The metabolic profiles in the excreta of rats and dogs were qualitatively similar but quantative differences were observed.

3. The main metabolites were products of (i) oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine, (ii) hydrolysis of the 5-isopropyl ester or 3-methyl ester group to carboxylic acid, and/or (iii) hydroxylation of the 6-methyl group or methyl group of the isopropyl ester chain.

4. Minor metabolites were products of hydrolysis from the 5-isopropyl ester to the carboxylic acid having a dihydropyridine ring, or reduction of the 3-nitro group of the phenyl moiety having a pyridine ring.     

Metabolism of nilvadipine, a new dihydropyridine calcium antagonist, in rats and dogs

1. The metabolic profiles of nilvadipine in the excreta of male rats and dogs were studied after i.v. and oral dosing. Six types of metabolites were isolated and identified from the urine of male rats and dogs or bile of rats. 2. Several metabolites were detected in the urine (12) and bile (17) of rats by two-dimensional t.l.c., after dosing with 14C-nilvadipine. The metabolic profiles in the excreta of rats and dogs were qualitatively similar but quantitative differences were observed. 3. The main metabolites were products of (i) oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine, (ii) hydrolysis of the 5-isopropyl ester or 3-methyl ester group to carboxylic acid, and/or (iii) hydroxylation of the 6-methyl group or methyl group of the isopropyl ester chain. 4. Minor metabolites were products of hydrolysis from the 5-isopropyl ester to the carboxylic acid having a dihydropyridine ring, or reduction of the 3-nitro group of the phenyl moiety having a pyridine ring.     

Disposition and metabolism of amosulalol hydrochloride,a new combined α- and β-adrenoceptor blocking agent,in rats,dogs and monkeys

1. The disposition and metabolism of amosulalol hydrochloride, a combined α- and β-adrenoceptor blocking agent, were studied in rats, dogs and monkeys.

2. After oral administration of [¹⁴C]amosulalol hydrochloride, the plasma concentration of radioactivity reached a maximum at 05 to 1 h in all species and declined with half-lives of about 2 h in both rats and monkeys, and of about 4 h in dogs. The ratios of unchanged drug to total radioactivity in the rat and dog plasma were 8 and 43% at 05 h after administration, respectively. The radioactivity in the rat tissues was high in the liver, kidney, blood and pancreas after oral administration.

3. Following oral dosage, the urinary excretion of radioactivity was 26-34% of the dose in rats, 45% in dogs and 46% in monkeys in 48 h. The biliary excretion after oral dosage amounted to 66% and 41% in rats and dogs, respectively.

4. Six metabolites were isolated and identified from the urine of rats and dogs. They were derived from one or two of the following pathways: I, hydroxylation of the 2-methyl group of the methylbenzenesulphonamide ring; II, demethylation of the o-methoxy group of the methoxyphenoxy ring; III, hydroxylation at the 4 or 5 position of the methoxy-phenoxy ring; IV, oxidative cleavage of the C—N bond yielding o-methoxyphenoxy acetic acid. Moreover, some metabolites were metabolized to glucuronide or sulphate.     

Comparative pharmacokinetics of nicardipine hydrochloride,a new vasodilator,in various species

1. The pharmacokinetics of a new potent vasodilator, 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nicardipine hydrochloride), were studied after oral and i.v. dosage to rats, dogs, monkeys and humans.

2. The plasma half-life and volume of distribution in humans after i.v. administration did not change with dosage in clinical range. In rats and dogs these parameters increased with higher doses, probably because of the potent vasodilative effect of the drug.

3. The plasma clearance in dogs and humans was not affected by dosage, but in rats tended to increase slightly with higher doses.

4. Systemic availability after oral administration was low in spite of excellent absorption, indicating a marked first-pass effect. Increased systemic availability with increased dose indicates that the metabolic activity of the liver may become partly saturated with the drug or its metabolites.

5. Disappearance of the drug from the plasma after i.v. administration was fastest in rats > dogs ≈ monkeys > humans. The terminal half-life of the drug after i.v. administration to humans was about 1?h.     

Absorption,excretion and metabolism of tiquizium bromide in dogs,and relationship between pharmacological effect and plasma levels of unchanged drug

1. The disposition of ¹⁴C-tiquizium bromide was investigated in dogs after oral administration and i.v. administration.

2. After oral administration, max. blood concn. of radioactivity were obtained from one to three hours after dosing. The half-lives of the terminal phase were 7.1?h (i.v.) and 9.4-12.0?h (p.o.). The relative bioavailability was 26%. The urinary excretion in three days was 24% (i.v.) and 5-9% (p.o.).

3. The most important mechanism of biotransformation was hydroxylation in the 5-position of the thiophene ring, and glucuronides of the isomeric hydroxylated products of tiquizium bromide were found in urine.

4. The time-course of the inhibitory effect of tiquizium bromide on stomach contraction correlated well with the plasma levels of unchanged drug after intraduodenal administration.     

Metabolism and disposition of [14C]5-amino-o-cresol in female F344 rats and B6C3F1 mice

The metabolism and disposition of [¹⁴C]5-amino-o-cresol (AOC) in female F344 rats following oral, intravenous, and dermal administration and in female B6C3F1 mice following oral administration were studied. Greater than 80% of a single oral dose (4.0–357 mg kg^?1) or intravenous dose (2.7 mg kg^?1) was excreted in urine within 24 h. When the dosing site was protected from grooming, less than 10% of the dermal dose (2.5 and 26 mg kg^?1, rinsed off after 6 h) was absorbed within 24 h, and most of the absorbed radioactivity was excreted in urine. For the unprotected dermal dose, grooming played a major role in the absorption of AOC. Very little AOC-derived radioactivity was present in the surveyed tissues after 24 or 72 h regardless of route, dose level, or species. Five urinary metabolites were identified: 5-acetamido-1,4-dihydroxy-2-methylbenzene glucuronide, AOC O-glucuronide, AOC O-sulfate, N-acetyl-AOC O-glucuronide, and N-acetyl-AOC O-sulfate.     

The metabolic fate of Sormodren (bornaprine hydrochloride) in animals and humans

1. Single oral doses of the anticholinergic drug [¹⁴C]Sormodren to rats (1?mg/kg), dogs (0.3?mg/kg) and humans (0.03?mg/kg) were well absorbed. Excreted in urine and faeces were means of 31 and 70%, 53 and 39%, and 78 and 4% in rats, dogs, and humans, respectively, during five days: excretion was prolonged and still incomplete at five days in humans.

2. Peak plasma levels of ¹⁴C (scaled for dose) were generally reached within 1–2h after oral doses in rats, 49 (ng/ml)/(mg/kg), dogs 290 (ng/ml)/(mg/kg) and humans 410(ng/ml)/(mg/kg), and declined with half-lives of approx. 5, 12 and 30?h, in these species respectively. Repeated oral doses of [¹⁴C]Sormodren to dogs resulted in some accumulation of ¹⁴C in the plasma.

3. Tissue concn. of ¹⁴C in dogs were generally higher than those in rats, particularly in the brain, lungs and eyes. The tissue distribution of ¹⁴C in rats and dogs was consistent with that of a compound readily eliminated by both renal and hepatic routes.

4. Basic metabolites in dog and human, urine and plasma were investigated using a combination of?h.p.l.c. and g.l.c.-mass spectrometry. Unchanged Sormodren was not detected in the dog samples and was only a minor component in human urine and plasma. Some metabolites were present as conjugates.

5. A basic extract of enzyme-hydrolysed dog urine (5?mg/kg dose) contained 42% of the urine ¹⁴C. The major metabolites in this fraction were identified as three isomers of monohydroxy-N-desethyl-Sormodren and three isomers of monohydroxy-Sormodren, resulting from hydroxylation in the bicyclic ring. The positions of oxidation were not determined. A similar extract from dog urine (0.3?mg/kg dose) contained 26% of the urine ¹⁴C and the major metabolites were identified as isomers of monohydroxy-N-desethyl-Sormodren.

6. A basic extract of enzyme-hydrolysed human urine (0.03?mg/kg dose) contained 23% of the urine ¹⁴C. The unchanged drug was only a minor component and most of the radioactivity was associated with five isomers of monohydroxy-Sormodren, hydroxylation having occurred in the bicyclic ring.

7. Basic extracts of dog and human plasma only contained about 10% of the plasma ¹⁴C. Metabolites were chromatographically similar to the hydroxylated metabolites identified in the corresponding urine samples.     

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine,a novel neuroprotective agent for ischemia-reperfusion damage,in rats

The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [¹⁴C]-KR31378 to rats. [¹⁴C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24?h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24?h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.     

Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. III. Species Differences in Metabolism

Abstract

1. After oral administration, the plasma concn. of TAI-284 reached a peak at 1 h (t_0·5 of 3·5 h) in mice, at 2 h (t_0·5 5 h) in rabbits and at 24 h (t_0·5 4·5 days) in guinea-pigs.

2. In mice and rabbits the major plasma metabolite was the pharmacologically active III (trans-4′-ol), but in guinea-pigs more than 97% of plasma radioactivity was accounted for by unchanged drug. Fraction II, containing an ulcerogenic metabolite, IIb (cis-3′-ol), was found in rat plasma but was not detected in the other 3 species.

3. In mice and rabbits, elimination of ingested radioactivity was completed in 72 h, while with guinea-pigs half the dose remained unexcreted at this time. In rats and mice, excretion in urine and faeces was almost equal, whereas in guinea-pigs and rabbits, more was excreted in urine than in faeces. The major urinary metabolites were the unidentified V and VI in rats and mice and metabolite III in guinea-pigs and rabbits.

4. Studies using liver homogenates or isolated liver profusion system demonstrated that limited hepatic entry of TAI-284 and lower enzyme activity were responsible for the slower metabolism in guinea-pigs.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

Metabolism of Linoleamides: II. Absorption,Distribution, Excretion and Metabolism of N-[α-Phenyl-β-(p-tolyl)ethyl] linoleamide

1. Absorption, distribution, excretion and metabolism of (-)N-[α-phenyl-β-(p-tolyl)ethyl][¹⁴C]linoleamide (¹⁴C-PTLA) were studied in rats and dogs. Faecal excretion of PTLA was studied in dogs and men by g.l.c.

2. ¹⁴C-PTLA (10 mg/kg) given orally to rats resulted in urinary and faecal excretion of radioactivity of 2 and 93 %, respectively, by male rats and 8 and 87% by female rats in 48 h. Faecal excretion of PTLA in men was similar to that in rats.

3. Distribution of radioactivity in rats and dogs after oral administration of ¹⁴C-PTLA showed that a major part of the dose was not absorbed.

4. N-[α-Phenyl-β-(p-tolyl)ethyl]succinic acid monoamide and N-[α-phenyl-β-(p-tolyl)ethyl]glutaric acid monoamide were detected in the urine of rats dosed orally with ¹⁴C-PTLA.     

Disposition and metabolism of indeloxazine hydrochloride,a cerebral activator,in rats

1. The disposition and metabolism of indeloxazine hydrochloride ((±) -2-[(inden-7-yloxy)methyl]morpholine hydrochloride) were studied in male Sprague-Dawley rats.

2. After oral administration of ¹⁴C-indeloxazine hydrochloride, the plasma concentration of total radioactivity reached a maximum at 15 min and declined with an apparent half-life of 2.2h in the first 6h period and declined more slowly thereafter. Unchanged drug in the plasma represented 13.5%, 5.9% and 0.4% of the total radioactivity at 15 min, 1 h and 6 h respectively after administration and levels decayed with a half-life of 0.9 h.

3. After oral and i.v. administration of the labelled compound, the urinary and faecal excretion of radioactivity in 72 h were 61–65% and 31–36% of the dose, respectively. Biliary excretion in bile duct-cannulated animals amounted to 49% of the dose in 72 h.

4. Seven metabolites have been isolated from the plasma or urine and characterized by i.r., n.m.r. and mass spectrometry. They were derived through dihydrodiol formation in the indene ring, hydroxylation of the indene ring and N-acetylation, oxidation and oxidative degradation of the morpholine ring. Some metabolites were excreted as their glucuronic acid or glucose conjugates. The major metabolite appcared to the trans-indandiol analogue of indeloxazine.

5. Possible metabolic pathways of degradation of the morpholine ring are discussed.     

The biotransformation of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. After oral or intravenous doses (0.25?mg/kg) of [¹⁴C]lormetazepam to rats, most of the urinary radioactivity was associated with polar components and < 1% dose was excreted as unconjugated lormetazepam. About 30% of an oral dose was excreted in rat bile as a conjugate of lormetazepam and about 50% dose as polar metabolites. Plasma also contained mainly polar metabolites, and unchanged lormetazepam represented at most 10% of total plasma radioactivity after an oral dose.

2. Almost all the radioactivity in dog, rhesus monkey and rabbit urine, after oral or intravenous doses (0.5–0.7?mg/kg) of [¹⁴C]lormetazepam, was associated with conjugated material. In the dog there were only two major components, conjugates of lormetazepam and lorazepam (N-desmethyl-lormetazepam) which accounted for about 24% and 14% respectively of the oral dose in the 0–24?h urine. The same two conjugated components were also present in dog bile. Conjugated lormetazepam was the only major component in monkey and rabbit urine and accounted for about 60% dose in the 0–24?h urine of each species, while conjugated lorazepam accounted for only about 0.5% and 4% respectively.

3. Dog and monkey plasma contained mostly conjugated material after oral and intravenous doses (0.05–0.07?mg/kg of [¹⁴C]lormetazepam. Dog plasma after an oral dose contained conjugates of both lormetazepam and lorazepam with peak concn. at 1?h of 130 and 47 ng/ml respectively. Concn. of these conjugates in plasma declined with apparent terminal half-lives of about 17 and 27?h respectively after oral doses, and 13?h in both cases after intravenous doses. Conjugated lormetazepam was the only major component in monkey plasma representing a peak concn. of 180 ng/ml at 1?h after an oral dose, and declined with an apparent terminal half-life of about 11?h after oral or intravenous doses.

4. Lormetazepam crosses the placental ‘barrier’ of rabbits: its concn. in the foetus were similar to those in maternal plasma after intravenous doses.     

The absorption,distribution and excretion of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. Oral doses of [¹⁴C]lormetazepam (0.05–0.25mg/kg) were rapidly and almost completely absorbed by female dogs, rabbits, rats and rhesus monkeys. Elimination of ¹⁴C was rapid and similar after oral or i.v. doses.

2. Rats excreted most of the dose in the faeces (76%), whereas dogs, rabbits and monkeys excreted it in the urine (60, 85 and 80% respectively. The urinary excretion half-lives of ¹⁴C from monkeys (c. 10?h), rabbits (c. 12?h), dogs (c. 14?h) and rats (c. 8?h) paralleled the rate of decline of plasma concn. of ¹⁴C.

3. Biliary excretion of lormetazepam and/or its metabolites occurred in rats (83%), dogs (48%) and possibly to a lesser extent in the other two species. Enterohepatic circulation of ¹⁴C in rat was extensive (47%), but not of long duration, and probably occurred in dog and rabbit.

4. Mean peak plasma concn. of ¹⁴C in dogs, rabbits, rats and monkeys of 190, 29, 42 and 280 ng equiv./ml respectively were reached at 1.5, 1, 0.5 and 1?h. A.U.C. values after oral and i.v. doses were similar in dogs, rats and monkeys. In these species, plasma concn. declined biphasically with t_1/2 values of about 15, 14 and 11?h respectively.

5. Concn. of ¹⁴C in rat tissues, particularly in blood cells, liver, kidneys and gut, were several times greater than those in plasma after single or multiple oral doses. Some accumulation in tissues occurred after multiple doses, presumably partly because of accumulation of ¹⁴C in blood cells.

6. Transplacental transfer of ¹⁴C into foetuses of rats or rabbits was low. In rabbits, maternal: foetal concn. ratios ranged between 9 and 26 : 1 after oral or i.v. doses.

7. The excretion (rats and dogs), or plasma ¹⁴C concn.-time profiles (dogs), were not altered during multiple oral doses for 21 days.     

Species Differences in Metabolism of Tiaramide Hydrochloride,a New Anti-inflammatory Agent

1. Urinary excretion of the radioactivity in 24?h after oral administration of [¹⁴C]tiaramide hydrochloride was 67% of the dose in mice, 59% in rats, 41% in dogs and 74% in monkeys.

2. The serum half-lives of tiaramide after intravenous administration were approximately 0·2?h in mice, 0·8?h in rats and 0·5?h in dogs.

3. Marked species variations were noted in the composition of metabolites in the serum and urinary radioactivity. The major metabolites found were 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR) and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineacetic acid (TRAA) in mice, TRAA and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-pipera-zineethanol 1-oxide (TRNO) in rats, TRNO and tiaramide-O-glucuronide (TR-O-Glu) in dogs, and TRAA and TR-O-Glu in monkeys.

4. The binding of tiaramide to plasma protein of the various species of animals and human was about 24–34% and the extent of the binding of tiaramide to human plasma protein was independent of drug concentration within the range of 1–100 μM.     

Metabolism and pharmacokinetics of the dihydropyridine calcium antagonist,ryosidine, in man

1. The metabolic fate of [¹⁴C]ryosidine (ryodipine) has been investigated after oral administration to human subjects (by capsule), and to rats and dogs (in solution). The excretion patterns of ¹⁴C were similar for all three species: about 50% dose was excreted in urine, mainly in 24 h, but a proportion was excreted slowly, particularly by humans. Absorption in man appeared to be less than in the animal species, probably as a result of the capsule dosage form used.

1 μg equiv./ml at four hours and declined biphasically thereafter (mean terminal t_1/2 = 28 h). Unchanged ryosidine was only detected in plasma from two to six hours (mean t_1/2 = 80 min), and never accounted for more than 5% of the plasma ¹⁴C. The extent of binding of ryosidine to the plasma proteins (in vitro) was similar (>90%) to that of total ¹⁴C (in vivo; mainly metabolites).

2. Mean concentrations of total ¹⁴C in human plasma reached a peak value of 0·4

3. Less than 0·5% of the dose to human subjects was excreted via the kidneys as unchanged ryosidine, whereas the bulk of the extractable faecal ¹⁴C was in the form of unchanged drug and presumably represented unabsorbed material. The principal routes of biotransformaiion of ryosidine in all three species involved oxidative aromatization of the 1,4-dihydropyridine ring, followed by ester hydrolysis, O-dealkylation, hydroxylation of an α-methyl group (and lactonization) and some glucuronidation, although quantitative inter-species differences were apparent.     

Distribution and excretion of methamphetamine and its metabolites in rats II. Time-course of concentration in blood and distribution after multiple oral administration

1. The time-course of total blood radioactivity after oral administration of ³H-methamphetamine, following multiple oral administration of non-radioactive methamphetamine for 7 and 14 days to rats, was examined to elucidate the effects of multiple administration on enterohepatic circulation.

2. Whole-body auto radiographs of rats after oral administration of ¹⁴C-methamphetamine showed high levels of radioactivity in contents of stomach and small intestine, bladder urine, liver, and various glands.

3. Distribution of methamphetamine and the major metabolite in tissues during multiple dosing was investigated; accumulation occurred in brain, liver, testis and fat.

4. Multiple oral administration of methamphetamine to rats slightly induced enzyme activities of N-demethylation and aromatic hydroxylation of methamphetamine in rat-liver 9000 g supernatant.     

Pharmacokinetics of NS-105, a novel cognition enhancer. 1st communication: absorption, metabolism and excretion in rats, dogs and monkeys after single administration of 14C-NS-105

The absorption, metabolism and excretion of NS-105 ((+)-5-oxo-D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition enhancer, were studied in rats, dogs and monkeys after intravenous or oral administration of 14C-NS-105. The protein binding of this drug was also investigated in vivo and in vitro. After the intravenous and oral administrations of 14C-NS-105, the unchanged drug accounted for most of the plasma radioactivity in all the species tested. After the intravenous injection, the plasma concentration of NS-105 decreased monoexponentially with respective elimination half-lives of 0.67, 2.1 and 1.3 h for the rats, dogs and monkeys. After the oral administration, the plasma concentration of NS-105 reached a maximum within 1 h, then decreased as in intravenous administration in all the species tested. NS-105 was almost completely absorbed from the small intestine, and first-pass metabolism was very limited. As a result, its systemic availability was high; 97% in the rats, 90% in the dogs and 79% in the monkeys. No significant sex-related differences in the plasma concentration profiles of radioactivity were observed in the rats after the oral administration of 14C-NS-105 (p > 0.05). Food affected the absorption of NS-105. The Cmax and AUC0-infinity of radioactivity concentration were proportional to the dose for 1-100 mg/kg of 14C-NS-105. There were no marked differences between the intravenous and oral routes in the compositions of urinary radioactivity for any of the species tested. In the urine of dogs, LAM-162 (oxidative metabolite with C-N cleavage of the piperidine ring), LAM-79 (metabolite with 4-hydroxylated piperidine ring), LAM-163 (metabolite with 3-hydroxylated piperidine ring) and M1 (not identified) accounted for 20%, 3%, 6% and 1% of the urinary radioactivity, respectively. In the urine of rats and monkeys, LAM-162 and LAM-79 accounted for 1-6% of the urinary radioactivity, but LAM-163 and M1 were not detected. After the intravenous and oral administrations, NS-105 was primarily eliminated by renal excretion in all the species tested, approximately 90% of the dose being excreted unchanged in the urine for rats and monkeys and 60% of it for dogs. Excretions of radioactivity in the bile and exhaled air in rats were less than 1.4% of the dose, and lymphatic absorption of radioactivity was only 0.3% of the dose. The percentage of 14C-NS-105 bound to serum proteins was less than 3.3% in all the animal species tested, including humans.     

Absorption, excretion and metabolism of tiquizium bromide in dogs, and relationship between pharmacological effect and plasma levels of unchanged drug

The disposition of 14C-tiquizium bromide was investigated in dogs after oral administration and i.v. administration. After oral administration, max. blood concn. of radioactivity were obtained from one to three hours after dosing. The half-lives of terminal phase were 7.1 h (i.v.) and 9.4-12.0 h (p.o.). The relative bioavailability was 26%. The urinary excretion in three days was 24% (i.v.) and 5-9% (p.o.). The most important mechanism of biotransformation was hydroxylation in the 5-position of the thiophene ring, and glucuronides of the isomeric hydroxylated products of tiquizium bromide were found in urine. The time-course of the inhibitory effect of tiquizium bromide on stomach contraction correlated well with the plasma levels of unchanged drug after intraduodenal administration.     

Biotransformation of nifedipine in rat and dog.

Following oral and/or intraduodenal administration, the biotransformation of 14C-labelled nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3, 5-dicarboxylate, Bay a 1040, Adalat, CAS 21829-25-4) has been reinvestigated in rats and dogs (dose: 5 mg/kg body weight in both species) to complete the metabolic data. Thirteen metabolites were isolated from the perfusate and bile of the isolated perfused rat liver model. Their structures were elucidated by spectroscopic methods (FAB-MS, combined GC/MS, NMR). The analyzed samples were used for the chromatographic (HPLC) comparison with urine and bile from the in vivo studies. The metabolites identified in rat urine (oral dose) account for 47.4% of the dose administered. 82.8% (rat) and 62.8% (dog) of the dose, resp., could be attributed to known structures in urine and bile following intraduodenal administration. Based on the structures identified the following biotransformation steps occurred: dehydrogenation of the 1,4-dihydropyridine system, hydroxylation of the methyl groups at 2- or 6-position followed by glucuronidation or by subsequent oxidation to the carboxylic acid, and oxidative ester cleavage.