Evaluation of the absorption, excretion, and metabolism of the antihypertensive agent RWJ-26899 in male and female CR Wistar rats and Beagle dogs.

The absorption, excretion and metabolism of N-(2, 6-dichlorophenyl)-beta-[[(1-methylcyclohexyl)methoxylmethyl]-N-(phenylmethyl)-1-pyrrolidineethanamine (RWJ-26899; McN-6497) has been investigated in male and female CR Wistar rats and beagle dogs. Radiolabeled [14C] RWJ-26899 was administered to rats as a single 24 mg/kg suspension dose while the dogs received 15 mg/kg capsules. Plasma (0-36 h; rat and 0-48 h; dog), urine (0-192 h; rat and dog) and fecal (0-192 h; rat and dog) samples were collected and analyzed. There were no significant gender differences observed in the data. The terminal half-life of the total radioactivity for rats from plasma was estimated to be 7.7 +/- 0.6 h while for dogs it was 22.9 +/- 4.4 h. Recoveries of total radioactivity in urine and feces for rats were 8.7 +/- 2.9% and 88.3 +/- 10.4% of the dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 4.1 +/- 1.4% and 90.0 +/- 4.7% of the dose, respectively. RWJ-26899 and a total of nine metabolites were isolated and tentatively identified in rat urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in rat urine and 8% in rat feces. RWJ-26899 and a total of four metabolites were isolated and identified in dog urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in urine and 63% in feces in dog. Five proposed pathways were used to describe the metabolites found in rats: N-oxidation, oxidative N-debenzylation, pyrrolidinyl ring hydroxylation, phenyl hydroxylation and methyl or cyclohexyl hydroxylation. Two biotransformation pathways in dogs are proposed: N-oxidation and methyl or cyclohexyl ring hydroxylation.     

Evaluation of the excretion and metabolism of the new analgesic agent RWJ-22757 in male and female CR Wistar rats

The excretion and metabolism of (+/-)-trans-3-(2-bromophenyl)octahydroindolizine hydrochloride (RWJ-22757) have been investigated in male and female CR Wistar rats. Radiolabeled [14C] RWJ-22757 was administered orally to each of the rats as a single 60 mg/kg suspension dose. Plasma (0-48 h), urine (0-168 h) and fecal (0-168 h) samples were collected and analyzed. There were no significant gender differences observed in the data. The estimated elimination half-life of the total radioactivity from plasma was 19 h while the estimated elimination half-life of RWJ-22757 was 15 h. Recoveries of total radioactivity in urine and feces were 58.4+/-5.8 and 42.4+/-6.3%, respectively. RWJ-22757 and a total of 11 metabolites were isolated in rat plasma, urine, and fecal extracts. The structures of four of these metabolites were tentatively identified. Unchanged RWJ-22757 accounted for < 4% of the dose in plasma and urine and 28% in feces; thus, indicating the drug was extensively metabolized and either not absorbed well or biliary excreted. Identified metabolites accounted for > 80% of the total radioactivity contained in the samples. The following pathways were used to describe the formation of the metabolites identified in rats: octahydroindolizine ring oxidation, phenyl hydroxylation, octahydroindolizine ring oxidation followed by ring opening to a carboxylic acid function and octahydroindolizine ring oxidation followed by ring opening and N-methylation.     

The metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in rats, dogs, and humans

Studies of the metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-[14C]cyanopyridine (I) have been performed in humans, dogs, and spontaneously hypertensive rats. After an iv injection of I (5 mg/kg), a substantial fraction of the radioactivity was excreted in the feces of rats (32%) and dogs (31%). After oral administration of I (5 mg/kg) the urinary recoveries of radioactivity for rat and dog were 19% and 53%, respectively, and represented a minimum value for absorption because of biliary excretion of radioactivity. In man, bililary excretion of I appeared to be of minor significance because four male subjects, after receiving 6 mg of I p.o., excreted 76% and 9% of the dose of radioactivity in the urine and feces, respectively. Unchanged I represented 58% of the radioactivity excreted in human urine. The half-life for renal elimination of I was determined to be 4.0 +/- 0.9 /hr. In contrast, unchanged I represented 7% and 1% of excreted radioactivity in rat and dog urine, respectively. A metabolite of I common to man, dog, and rat was identified as 5-hydroxy-I, which represented approximately 5% of the excreted radioactivity in all species. Minor metabolites of I in which the pyridine nucleus had undergone additional hydroxylation were present in dog urine along with an oxyacetic acid metabolite, also bearing a hydroxylated pyridine nucleus.     

Pharmacokinetics of nisoldipine. I. Absorption, concentration in plasma, and excretion after single administration of [14C]nisoldipine in rats, dogs, monkey, and swine

The absorption, disposition and excretion of (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) have been studied following a single administration of the 14C-labelled compound to rats, dogs, monkey and swine via different routes (intravenous, oral, intraduodenal) in the dose range of 0.05-10 mg.kg-1. [14C]nisoldipine was absorbed rapidly and almost completely. Peak concentrations of radioactivity in plasma were reached 0.9 h (rat), 1.4 h (dog), and 3.6 h (monkey) after oral administration with normalized maximum concentrations being in the same range for all three species (0.49-0.79). The radioactivity was eliminated from plasma with half-lives between 42 h and 54 h within an observation period up to 3 days. The contribution of unchanged [14C]nisoldipine to the concentration of total radioactivity in plasma was low after oral administration (between 0.5% (monkey) and 3.4% (dog) in the peak) indicating an extensive presystemic elimination of this compound. The bioavailability was estimated at 3.4% in rats and 11.7% in dogs. [14C]nisoldipine was highly bound to plasma proteins with free fractions of 0.9-2.9%. The excretion of the radioactivity via urine and feces/bile both after oral and intravenous administration of [14C]nisoldipine occurred rapidly and almost completely within 48 h in all species. Very small residues in the body were recovered at the end of the experiments in rats and dogs (less than 1.6% of the dose). The biliary/fecal route of excretion was preferred in rats, dogs and swine, whereas in monkey 76% of the dose was excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).     

Disposition of radiolabeled BMS-204352 in rats and dogs

BMS-204352, a maxi-K channel opener, is currently under development for the treatment of stroke. The objective of this study was to determine the pharmacokinetics, mass balance and absolute oral bioavailability of [(14)C]-BMS-204352 in rats and dogs. [(14)C]-BMS-204352 was administered, to rats (n=10/group; parallel design, 6 mg/kg) and dogs (n=4/group; crossover design, 2 mg/kg), as an oral (PO) or as a 3-min intraarterial (IA) infusion in rats and a 6-min intravenous (i.v.) infusion in dogs. Blood, urine, and feces samples were collected and analyzed for unchanged BMS-204352 (plasma) using a validated LC/MS assay and for total radioactivity (plasma, urine, feces) using liquid scintillation counting. The mean total body clearance (CLT) and steady-state volume of distribution (VSS) values for the unchanged BMS-204352 were 2.58 +/- 0.48 l/h/kg and 6.3 +/- 1.14 l/kg, respectively, in rats and 0.21 +/- 0.02 l/h/kg and 4.06 +/- 0.47 l/kg, respectively, in dogs. In both species, the elimination half-life of total radioactivity was significantly longer as compared to the unchanged drug. After IA administration of radiolabeled BMS-204352 to rats, ca. 5.9 and 85% of radioactivity was recovered within 7 days in urine and feces, respectively; corresponding recoveries after PO dosing were 4.5 and 99.5%, respectively. The recoveries were similar in dogs, i.e., ca. 5.2 and 83% of administered radioactivity recovered in urine and feces, respectively, for IV dose and ca. 4 and 86%, respectively, for PO dose. These data indicate that nonrenal (biliary) elimination in both species was predominant. Based on comparable urinary recovery of radioactivity and plasma AUCs of radioactivity, the extent of oral absorption of BMS-204352 appeared to be complete in both species. The absolute oral bioavailability was 55% in rats and 79% in dogs. Bioavailability and extent of absorption data suggest evidence of first pass metabolism of BMS-204352 in the rat and dog.     

Metabolic fate of premazepam, a new anti-anxiety drug, in the rat and the dog

A study of the disposition and metabolism of premazepam, 3,7-dihydro-5-phenyl-6,7-dimethyl-pyrrole[3,4-e][1,4]diazepin-2-(1 H) -one, a new anti-anxiety agent, was carried out in rats and dogs given the 14C-labeled compound iv and po. In both species, after oral administration, both total radioactivity and the unchanged drug are rapidly absorbed and peak plasma levels are reached within 0.5-1 hr in rats and 2 hr in dogs. Unchanged premazepam is cleared faster in rats than in dogs, with half-lives about 1.7 and 2.7 hr, respectively. Following oral dosage, two-thirds of the dose is eliminated in urine. From the urine of the two species, eight metabolites and unchanged premazepam were identified. N-7-Desmethyl premazepam (l) is the major metabolite in rat urine (18% of the dose) but is not present in dog urine, while 6-hydroxymethyl premazepam is the most abundant metabolite in dog urine (25% of the dose) but is absent in rat urine. Metabolites III and IV from rat and dog urine are stable derivatives of the intermediate formed by the cleavage of the imine bond of the diazepine ring. A successive hydrolysis of the amidic bond of the same intermediate originates metabolites V-VIII, which are quantitatively minor ones.     

Pharmacokinetics of nimodipine. I. Communication: absorption, concentration in plasma and excretion after single administration of [14C]nimodipine in rat, dog and monkey

Studies on absorption, plasma concentrations and excretion with (+/-)isopropyl-2-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nimodipine, Bay e 9736, Nimotop) have been conducted in rat, dog and monkey using the carbon-14-labelled substance and a wide range of doses (0.05-10 mg/kg) administered via different routes (intravenous, oral, intraduodenal). Nimodipine was well absorbed in all species. Peak plasma concentrations of radioactivity were determined 28-40 min (male rat), 60 min (female rat), about 3 h (dog) and 7 h (monkey) after administration. Dependent on the observation period (24-216 h) terminal half-lives for the elimination of radioactivity from plasma ranging between 4.6 h (female rat) and 157 h (dog) were observed. Comparing the AUC, the concentration of unchanged [14C]nimodipine in plasma represented only a small (maximally 37% in dogs after i.v. dose) to negligible (about 1%, monkey after oral dosing) part of the total radioactivity. Excretion of radioactivity via feces and urine was rapid in all species after both oral and intravenous dosing. Fecal (biliary) excretion was the major excretory route in rat and dog. The monkeys excreted about 40 to 50% via the urine. Residues in the body never exceeded 1.5% of the dose. [14C]nimodipine and/or its radiolabelled metabolites were secreted in milk of orally dosed lactating rats. Binding of [14C]nimodipine to plasma proteins of rat and dog was about 97%.     

Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs.

The in vivo metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-], a novel neuromodulator, were investigated in mice, rats, rabbits, and dogs after oral administration of (14)C-RWJ-333369. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. In almost all species, the administered radioactive dose was predominantly excreted in urine (>85%) with less than 10% in feces. Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Unchanged drug excreted in urine was minimal (<2.3% of the administered dose) in all species. The primary metabolic pathways were O-glucuronidation (rabbit > mouse > dog > rat) of RWJ-333369 and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid. The latter metabolite was subsequently metabolized in parallel to 2-chlorophenylglycine and 2-chlorobenzoic acid (combined hydrolytic and oxidative pathways: rat > dog > mouse > rabbit). Other metabolic pathways present in all species included chiral inversion in combination with O-glucuronidation and sulfate conjugation (directly and/or following hydroxylation of RWJ-333369). Species-specific pathways, including N-acetylation of 2-chlorophenylglycine (mice, rats, and dogs) and arene oxidation followed by glutathione conjugation of RWJ-333369 (mice and rats), were more predominant in rodents than in other species. Consistent with human metabolism, multiple metabolic pathways and renal excretion were mainly involved in the elimination of RWJ-333369 and its metabolites in animal species. Unchanged drug was the major plasma circulating drug-related substance in the preclinical species and humans.     

The metabolism of talampicillin in rat, dog and man

1. After administration of [phthalidyl-14C] talampicillin (Talpen) to rat, dog and man, radioactivity was excreted mainly in the urine (90%, 86% and 98% in rat, dog and man respectively). 2. After administration of [ampicillin-14C] talampicillin, radioactivity was excreted in the urine of rats and dogs to a lesser extent (35% in both species) and only a small proportion of the dose was excreted in the bile (6% in rats, less than 0.1% in dogs). 3. The pattern of radiometabolites was very similar in extracts of the urines of radiometabolites was very similar in extracts of the urines of rat, dog and man dosed orally with [phthalidyl-14C]talampicillin. The major metabolite was 2-hydroxymethylbenzoic acid. 4. Unchanged talampicillin was present in the hepatic portal vein blood of dog and thus reached the liver, whereas in rat, no parent compound could be detected in portal vein blood. This result may help to explain differences in toxicity of the compound in rat and dog. 5. Studies in vitro showed that the intestinal wall is an important site of hydrolysis of talampicillin in rat and dog.     

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate in rats, dogs and monkeys

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) were studied in rats, dogs and monkeys after administration of [14C]-MN-1695. MN-1695 was found to be well absorbed from the small intestine after oral administration in all species examined. Plasma level of unchanged MN-1695 reached a maximum at 1 to 4 h after oral administration of [14C]-MN-1695 in rats, dogs and monkeys. The mean elimination half-life of unchanged MN-1695 from plasma was about 3, 4 and 50 h in rats, dogs and monkeys, respectively. Tissue levels of radioactivity after oral administration of [14C]-MN-1695 in rats indicated that [14C]-MN-1695 was distributed throughout the body and the radioactivity in tissues disappeared with a rate similar to that in plasma. A stomach autoradiogram after intravenous administration of [14C]-MN-1695 in the rat revealed the radioactivity localized in the gastric mucosa where MN-1695 was assumed to exert its pharmacological activity. In pregnant rats, [14C]-MN-1695 was distributed to the fetus with levels similar to maternal blood levels. After oral administration of [14C]-MN-1695 in rats, 39 to 46% of the dose was excreted into the urine and 50 to 63% of the dose into the feces, within 96 h. In dogs, about 40% of the dose was excreted into the urine and about 50% of the dose into the feces, within 6 days after oral administration. In monkeys, within 14 days after oral administration, about 60 and 30% of the dose were excreted into the urine and feces, respectively, and the main excretion route was the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Metabolism of Talampicillin in Rat,Dog and Man

1. After administration of [phthalidyl-¹⁴]talampicillin (Talpen® to rat. dog and man, radioactivity was excreted mainly in the urine (90%, 86% and 98% in rat, dog and man respectively).

2. After administration of [ampicillin-¹⁴C]talampicillin, radioactivity was excreted in the urine of rats and dogs to a lesser extent (35% in both species) and only a small proportion of the dose was excreted in the bile (6% in rats, less than 0·1% in dogs).

3. The pattern of radiometaboletes was very similar in extracts of the urines of rat, dog and man dosed orally with [phthalidyl-14C]talampicillin. The major metabolite was 2-hydroxymethylbenzoic acid.

4. Unchanged talampicillin was present in the hepatic portal vein blood of dog and thus reached the liver, whereas in rat, no parent compound could be detected in portal vein blood. This result may help to explain differences in toxicity of the compound in rat and dog.

5. Studies in vitro showed that the intestinal wall is an important site of hydrolysis of talampicillin in rat and dog.     

Pharmacokinetics and excretion of hydroxysafflor yellow A, a potent neuroprotective agent from safflower, in rats and dogs

Studies were conducted to characterize the pharmacokinetics and excretion of hydroxysafflor yellow A (HSYA) in rats and dogs after administration by intravenous injection or infusion. Plasma, urine, feces and bile concentrations of HSYA were measured using five validated mild HPLC methods. Linear pharmacokinetics of HSYA after the intravenous administrations were found at doses ranging from 3 to 24 mg/kg in rats and from 6 to 24 mg/kg in dogs. At a dose of 3 mg/kg, HSYA in urine, feces and bile was determined. For 48 h after dosing, the amount of urinary excretion accounted for 52.6 +/- 17.9 % (range: 31.1 - 78.7%, n = 6) of the dose, and the amount of fecal amount accounted for 8.4 +/- 5.3% (range 1.7 - 16.4%, n = 6) of the dose. Biliary excretion amount accounted for 1.4 +/- 1.0% (range 0.4-2.9%; n = 6) of the dose for 24 h after dosing. Percent plasma protein binding of HSYA ranged from 48.0 to 54.6% at 72 h. In summary, five mild HPLC methods for the determinations of HSYA in rat plasma, urine, feces, bile and dog plasma have been developed and successfully applied to preclinical pharmacokinetics and excretion of HSYA in rats and dogs. The results of excretion studies indicated that HSYA was rapidly excreted as unchanged drug in the urine. In view of previous pharmacological work, the concentration-dependent neuroprotective effect of HSYA in rats was defined.     

Excretion of radioactivity from rats and rabbits following cutaneous application of two 14C-labeled azo dyes

A benzidine-derived azo dye, C.I. direct black 38 (DB38), and a p-phenylenediamine-derived dye, C.I. direct black 19 (DB19), labeled with carbon-14 in their aromatic amine moieties, were applied to the shaved dorsal skin of male Fischer-344 rats and New Zealand rabbits. Application sites were protected with nylon gauze and elastic bandage assemblies. Following application of measured amounts of radiolabeled dye in 0.1 M pH 10.2 carbonate buffer, serial urine and fecal samples were obtained from individual animals in metabolism cages at 24, 48, 72, 96, 120, and 144 h. Aliquots of urine and fecal homogenates were assayed for radioactivity by scintillation counting. Cumulative excretion of radioactivity from rats receiving DB38 was 0.05% of total dermal dose at 144 h in urine, and 0.16% of total dermal dose in feces. Cumulative excretion of radioactivity from DB38-treated rabbits at 144 h was 3.12% of total dermal dose in urine, and 5.12% in feces. From rats and rabbits receiving topical DB19, cumulative excretion of radioactivity at 144 h was less than that from DB38-treated animals. In rat urine, 0.04% of total dermal dose appeared; in rat feces, no radioactivity was recovered. In rabbit urine, 0.04% of dermal dose was found; 0.01% appeared in rabbit feces.     

Metabolism of captopril-L-cysteine,a captopril metabolite,in rats and dogs

1. The metabolism of [¹⁴C]captopril-L-cysteine was studied in spontaneously hypertensive rats and pure-bred beagles after a single i.v. dose (4?mg/kg).

2. During the first 24?h, concn. of total radioactivity in blood were similar in both species.

3. Captopril was found in small amounts in the blood of both species. In rats, captopril, bound covalently but reversibly to plasma proteins (CP-PR), was the major component in blood (70%), whereas captopril-L-cysteine was a minor component (23%) of the total radioactivity. In dog blood, CP-PR constituted a smaller fraction (45%) of the total radioactivity than in the rat and captopril-L-cysteine was the major component (53%).

4. In 72?h, 89–91% of the dose was excreted in the urine of rats and dogs. Captopril-L-cysteine accounted for 7% (rat) and 68% (dog) of the radioactivity in urine; captopril accounted for 75% (rat) and 7% (dog). Other metabolites were present in the urine of both species.

5. The greater net conversion of captopril-L-cysteine to CP-PR and to captopril in rats helps explain why captopril-L-cysteine is excreted in urine as a major metabolite of captopril in dogs but only a minor one in rats.     

Evaluation of the absorption, excretion and metabolism of [14C] etoperidone in man.

1. The absorption, excretion and metabolism of 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-4,5-diethyl-2,4-dihydro-3H-1,2,4- triazole-3-one hydrochloride (etoperidone HCl) was investigated in six healthy men. Subjects were tasted overnight before receiving a single oral dose of a 100 mg solution [14C] etoperidone HCl. 2. Plasma (0-48 h), urine (0-120 h) and faecal (0-120 h) samples were collected. The terminal half-life of the total radioactivity from plasma was 21.7 +/- 2.8h with an apparent clearance of 1.01 +/- 0.08 ml min(-1). Recoveries of total radioactivity in urine and faeces were 78.8 +/- 3.6% and 9.6 +/- 4.1% of the dose, respectively. 3. Etoperidone and 21 metabolites were isolated and identified in the plasma, urine and faecal extracts. Unchanged etoperidone accounted for <0.01% of the dose in all excreta samples. Nine metabolites were identified in the plasma extracts and 21 urinary metabolites were identified. Seven faecal metabolites were identified. 4. Five proposed pathways were used to describe the formation of the metabolites: alkyl oxidation, piperazinyl oxidation, N-dealkylation, phenyl hydroxylation and conjugation. Alkyl oxidation of etoperidone resulted in the formation of 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-4-ethyl-2,4-dihydro-5- (1-hydroxyethyl)-3H-1,2,4-triazole-3-one. Piperazinyl oxidation of this metabolite leads to the formation of its N-oxide. N-dealkylation of the piperazinyl group led to the formation of 1-(3-chlorophenyl) piperazine and triazole propionic acid. Phenyl hydroxylation led to three important metabolites in the urine and faeces.     

Comparative study on the disposition of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and dopamine hydrochloride in rats and dogs

The pharmacokinetics of a dopamine derivative, TA-870, and dopamine (DA) after oral administration are compared in rats and dogs. The maximum concentrations of free DA in plasma after oral administration of TA-870 were 150 ng/ml in the rat (30 mg/kg) and 234 ng/ml in the dog (33.5 mg/kg). On the contrary, the maximum plasma concentrations after oral administration of DA at an equimolar dose to TA-870 were 12 ng/ml in the rat (12 mg/kg) and 36 ng/ml in the dog (13.5 mg/kg). The AUC values of free DA in plasma after oral administration of TA-870 (30 or 33.5 mg/kg) were 4-6 times higher than those after DA in both animal species. The peak tissue levels of radioactivity in rats after oral administration of [14C]TA-870 (30 mg/kg) were also 5.5 times higher in the liver and 1-2 times higher in other tissues than those after [14C]DA dose (12 mg/kg). In rats, the main excretion route of radioactivity after oral administration of [14C]TA-870 or DA was via the urine. The total recoveries of radioactivity in the urine and feces were 91-96% of the dose within 24 hr for both compounds. Biliary excretion in rats accounted for 19.8% of the dose of [14C]TA-870 and 12.6% of the dose of [14C]DA within 24 hr. These results demonstrate that TA-870 was well absorbed from the digestive tract, extensively metabolized to dopamine, and proved to be an orally usable dopamine prodrug.     

Metabolism, pharmacokinetics, and protein covalent binding of radiolabeled MaxiPost (BMS-204352) in humans.

MaxiPost [(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); BMS-204352] is an investigational maxi-K channel opener to treat ischemic stroke. This study reports the disposition, metabolism, pharmacokinetics, and protein covalent binding of (14)C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg (14)C-labeled BMS-204352 (50 microCi) as a 5-ml intravenous infusion lasting 5 min, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially, followed by a terminal decline. The mean terminal t(1/2) of plasma radioactivity (259 h) was prolonged compared with that of unchanged parent (37 h). Furthermore, the extractability of radioactivity in plasma decreased over time, reaching approximately 20% at 4 h after dosing. The unextractable radioactivity was covalently bound to plasma proteins through a des-fluoro-des-methyl BMS-204352 lysine adduct. Unchanged BMS-204352 and minor metabolites were identified in plasma extract following protein precipitation. The recovery of the radioactive dose in urine and feces was nearly complete in 14-day collections (approximately 37% in urine and 60% in feces). The N-glucuronide of the parent was the prominent metabolite in urine (16.5% of dose), whereas the parent was a major drug-related component in feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of (14)C-labeled BMS-204352 were observed in humans, dogs, and rats.     

Distribution and metabolism of the antipsychotic agent mazapertine succinate in rats

The pharmacokinetics and drug disposition of 14C 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoy]piperidine succinate (RWJ-37796, mazapertine, Mz) have been investigated in male and female Sprague-Dawley rats. Approximately 93% of the orally administered radioactive dose (30 mg/kg) was recovered after 7 days. Fecal elimination accounted for approximately 63% of the dose while urine accounted for 30%. The rate of elimination of 14C Mz was rapid with 81% of the total fecal and 94% of the total urinary radioactivity being excreted within 24 h. There were no significant gender differences in the overall excretion pattern. The maximal plasma concentration of Mz and total radioactivity occurred at 0.5h after dosing and plasma concentrations were consistently higher in female rats. The Mz concentration declined rapidly in plasma with a terminal half-life<2 h. The total radioactive dose in plasma displayed a considerably longer terminal half-life of 9-13 h. Mz and a total of 15 metabolites were isolated and identified in these samples. Unchanged Mz accounted for <5% of the radioactive dose in excreta samples and <8% of the sample in plasma (0-24 h). Metabolites were formed by phenyl hydroxylation, piperidyl oxidation, O-dealkylation, N-dephenylation, oxidative N-debenzylation and glucuronide conjugation.     

Species-differences in disposition and reductive metabolism of methoxymorpholinodoxorubicin (PNU 152243), a new potential anticancer agent.

Plasma pharmacokinetics, excretion balance and urinary metabolites of methoxymorpholino doxorubicin (MMDX) were investigated in male and female rats and in female dogs after i.v. administration of the(14)C-labelled drug. The mean total recovery of radioactivity in 96 h (urine plus faeces) was approximately 74 and 60% dose in male and female rats, respectively, while in female dogs approximately 72% dose was recovered in 336 h. Most of the radioactivity was present in faeces, with the urinary elimination accounting for only 3-4% dose in rats and dogs. These data suggest that biliary excretion is an important route of elimination of MMDX and/or its metabolites in both species. No differences were observed in the urinary metabolic profile of male and female rats. Two main peaks were present in radiochromatograms of urine from rats and dogs, i.e. MMDX and its 13-dihydro metabolite (MMDX-ol), accounting for approximately 25 and 20% of total radioactivity in 0-24-h urine in rats and 30 and 36% in dogs. The MMDX-ol/MMDX ratio in dog urine was higher than that observed in rat urine. No aglycones were detected in the urine samples from either species. In the rat, the plasma concentration-time profile suggested that the disposition of MMDX, MMDX-ol and total radioactivity is not sex-dependent. MMDX was the major species present in the systemic circulation; its AUC (0-96 h) accounted for 70% of total plasma radioactivity with the sum of AUC (MMDX) plus AUC (MMDX-ol) accounting for 77% of total radioactivity. In the dog, the sum of AUC (MMDX) plus AUC (MMDX-ol) amounted to 8% of radioactivity AUC(0-t(z) indicating that an important proportion of other(s) unknown metabolite(s) is present in dog plasma. Plasma levels of MMDX-ol in the rat were approximately 10-fold lower than those of the parent compound, whereas they were three times higher than those of MMDX in the dog. These data show that the reduction of the 13-keto group of MMDX is species-dependent, and occurs preferentially in the dog compared to the rat.