Evaluation of the excretion, and metabolism of the cardiotonic agent bemoradan in male rats and female beagle dogs.

The excretion and metabolism of (+/-) [6-(3,4-dihydro-3-oxo-1,4[2H]-benzoxazine-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one] (bemoradan; RWJ-22867) have been investigated in male Long-Evans rats and female beagle dogs. Radiolabeled [14C] bemoradan was administered to rats as a singkle 1 mg/kg suspension dose while the dogs received 0.1 mg/kg suspension dose. Plasma (0-24 h; rat and dog), urine (0-72 h; rat and dog) and fecal (0-72 h; rat and dog) samples were collected and analyzed. The terminal half-life of the total radioactivity for rats from plasma was estimate to be 4.3 +/- 0.1 h while for dogs it was 7.5 +/- 1.3 h. Recoveries of total radioactivity in urine and feces for rats were 49.1 +/- 2.4% and 51.1 +/- 4.9% of th dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 56.2 +/- 12.0% and 42.7 V 9.9% of the dose, respectively. Bemoradan and a total of nine metabolites were isolated and tentatively identified in rat and dog plasma, urine, and fecal extracts. Unchanged bemoradan accounted for approimately < 2% of the dose in rat urine and 20% in rat feces. Unchanged bemoradan accounted for approximately 5% of the dose in urine and 16% in feces in dog. Six proposed pathways were used to describe the metabolites found in rats and dogs: pyridazinyl oxidations, methyl hydroxylation, hydration, N-oxidation, dehydration and phase II conjugations.     

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.     

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 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.     

Metabolism of the new nonbenzodiazepine anxiolytic agent, RWJ-51204, in mouse, rat, dog, monkey and human hepatic S9 fractions, and in rats, dogs and humans.

The in vitro and in vivo metabolism of the nonbenzodiazepine anxiolytic agent, RWJ-51204 was investigated after incubation with mice, rat, dog, monkey, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral dose administration to rats (100 mg/kg), dogs (5 mg/kg), and humans (2.5 mg/subject). Plasma and red blood cells (2 h, rat) and urine samples (0-24 h, rat, dog and human) were obtained postdose. Unchanged RWJ-51204 (39-93% of the sample in vitro; < or =5% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data, and by comparison of synthetic samples. The in vitro and in vivo metabolic pathways for RWJ-51204 are proposed, and the metabolite formations are via the following five pathways: 1. phenyl oxidation, 2. pyrido-oxidation, 3. N-deethoxymethylation, 4. dehydration, and 5. glucuronidation. Pathway 1 formed 4-hydroxy-2-fluoro-phenyl-RWJ-51204 (M1, 7-24% in vitro; 5-60% in vivo) in major amounts, OH-benzimidazole-RWJ-51204 (M2, 5-8% in vitro and in vivo) and diOH-phenyl-RWJ-51204 (< or =5-16% in vitro and in vivo); in conjunction with pathway 5 produced M1 glucuronide (60% in rat & dog; 17% in human), M2 glucuronide (16% in human). Pathways 2-4 formed minor/trace oxidized, and dehydrated metabolites. RWJ-51204 is extensively metabolized in vitro (except dog) and in vivo in rats, dogs and humans.     

Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog.

1. Metabolism of the analgesic agent, tramadol hydrochloride, was investigated after a single oral administration of 14C-tramadol to four rats (50)mgkg(-1) and two dogs (20)mg kg(-1). 2. Recovery of total radioactivity in rat and dog urine samples over 24 h was 73 and 65% of the radioactive dose, respectively. 3. Unchanged tramadol and a total of 24 metabolites, consisting of 16 Phase I metabolites and eight conjugates (seven glucuromides, one sulphate), were isolated and tentatively identified, which accounted for > 52% of the dose in urine of both species. 4. Of the metabolites, five (M1-5) were previously identified. 5. The metabolites were formed via the following six metabolic pathways: O-demethylation, N-demethylation, cyclohexyl oxidation, oxidative N-dealkylation, dehydration and conjugation. 6. Pathways 1-3 appear to be major steps, forming seven O-desmethyl/N-desmethyl and hydroxy-cyclohexyl metabolites in major quantities. 7. Pathways 1-3 in conjunction with pathway 6 produced four glucuronides along with four minor conjugates. 8. In addition, the in vitro metabolism of tramadol was conducted using rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged tramadol (30% of the sample) plus nine metabolites, M1-7, tramadol-N-oxide (M31) and OH-cyclohexyl-M1 (M32), were profiled and tentatively identified based on MS and MS/MS data.     

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.     

Biotransformation of the antipsychotic agent, mazapertine, in dog--mass spectral characterization and identification of metabolites.

1. Biotransformation of the antipsychotic agent, mazapertine, was studied after a single oral administration of 14C-mazapertine succinate (10 mg/kg, free base) to six beagle dogs (three male, three female). 2. Following oral administration of 14C-mazapertine, plasma (0-48 h), urine (0-7 days), and faeces (0-7 days) were collected. Recoveries of total radioactivity in urine and faeces were 26.9 and 62.0% of the dose, respectively. 3. Unchanged mazapertine plus 14 metabolites were isolated and identified, which accounted for > 60% of the sample radioactivity in the plasma, 17% of the dose in urine and 28% of the dose in faecal extract. 4. Unchanged mazapertine accounted for < 4% of the radioactive dose in excreta samples and < 21% of the sample radioactivity present in plasma samples. 5. Seven metabolic pathways for the formation of metabolites were identified including: (1) phenyl hydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) N-dephenylation, (5) oxidative N-debenzylation, (6) depiperidylation and (7) conjugation. 6. Pathways 1, 2, 5 and 6 produced 4-OH-piperidyl, OH-phenyl-OH-piperidyl, carboxybenzoyl piperidine and depiperidyl analogues of mazapertine as major metabolites.     

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.     

Biotransformation of the antipsychotic agent,mazapertine, in dog-mass spectral characterization and identification of metabolites

1. Biotransformation of the antipsychotic agent, mazapertine, was studied after a single oral administration of ¹⁴C-mazapertine succinate (10?mg/kg, free base) to six beagle dogs (three male, three female). 2. Following oral administration of ¹⁴C-mazapertine, plasma (0-48 h), urine (0-7 days), and faeces (0-7 days) were collected. Recoveries of total radioactivity in urine and faeces were 26.9 and 62.0% of the dose, respectively. 3. Unchanged mazapertine plus 14 metabolites were isolated and identified, which accounted for &;gt;60% of the sample radioactivity in the plasma, 17% of the dose in urine and 28% of the dose in faecal extract. 4. Unchanged mazapertine accounted for &;lt;4% of the radioactive dose in excreta samples and &;lt;21% of the sample radioactivity present in plasma samples. 5. Seven metabolic pathways for the formation of metabolites were identified including: (1) phenyl hydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) Ndephenylation, (5) oxidative N-debenzylation, (6) depiperidylation and (7) conjugation. 6. Pathways 1, 2, 5 and 6 produced 4-OH-piperidyl, OH-phenyl-OH-piperidyl, carboxybenzoyl piperidine and depiperidyl analogues of mazapertine as major metabolites.     

Disposition and biotransformation of quinpirole, a new D-2 dopamine agonist antihypertensive agent, in mice, rats, dogs, and monkeys

The disposition and metabolism of quinpirole were studied in rats, mice, dogs, and monkeys. A single 2 mg/kg dose of 14C-quinpirole was administered orally to rats, mice, and monkeys. Dogs were given a single 0.2 mg/kg iv dose of 14C-quinpirole. Of the dose administered, 75-96% was recovered in the urine within 72 hr, with the majority being excreted during the first 24 hr. Peak plasma concentrations of radioactivity and quinpirole were coincident and were observed within 0.25 hr in rodents and at 2 hr in monkeys. Unchanged quinpirole accounted for 0.9%, 36%, and 69% respectively. Biotransformation of quinpirole was compared by quantitating the urinary metabolites by HPLC. The percentage of the radioactivity in urine representing unchanged drug was determined for each species: monkey (3%), dog (13%), mouse (40%), and rat (57%). The majority of 14C-quinpirole was shown to be biotransformed in rats, mice, and monkeys through common metabolic pathways but to various extents. Most metabolites resulted from structural alterations (N-dealkylation, lactam formation, omega and omega-1 hydroxylation) that centered around the piperidine ring portion of the molecule. These metabolites were less important in dogs. The major metabolic pathway in dogs involved hydroxylation of a methylene carbon adjacent to the pyrazole nucleus of quinpirole followed by O-glucuronidation. Evidence of metabolism of the pyrazole moiety was found in the isolation of an N-glucuronide conjugate of quinpirole from monkey urine.     

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).     

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.     

Metabolism of the analgesic drug,tramadol hydrochloride,in rat and dog

1. Metabolism of the analgesic agent, tramadol hydrochloride, was investigated after a single oral administration of ¹⁴C-tramadol to four rats (50mg kg^-1) and two dogs (20?mg kg^-1). 2. Recovery of total radioactivity in rat and dog urine samples over 24h was 73 and 65% of the radioactive dose, respectively. 3. Unchanged tramadol and a total of 24 metabolites, consisting of 16 Phase I metabolites and eight conjugates (seven glucuronides, one sulphate), were isolated and tentatively identified, which accounted for &;gt; 52% of the dose in urine of both species. 4. Of the metabolites, five (M1-5) were previously identified. 5. The metabolites were formed via the following six metabolic pathways: O-demethylation, N-demethylation, cyclohexyl oxidation, oxidative N-dealkylation, dehydration and conjugation. 6. Pathways 1-3 appear to be major steps, forming seven O-desmethyl/N-desmethyl and hydroxy-cyclohexyl metabolites in major quantities. 7. Pathways 1-3 in conjunction with pathway 6 produced four glucuronides along with four minor conjugates. 8. In addition, the in vitro metabolism of tramadol was conducted using rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged tramadol (30% of the sample) plus nine metabolites, M1-7, tramadol-N-oxide (M31) and OH-cyclohexyl-M1 (M32), were profiled and tentatively identified based on MS and MS/MS data.     

The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-) in humans.

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulator in clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of (14)C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 +/- 6.6%) and much less in feces (2.5 +/- 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species.     

Biotransformation of bromperidol in rat, dog, and man

The metabolic fate of 14C-bromperidol after po administration was studied in rat, dog, and man. When 14C-bromperidol was given to female Wistar rats, 23-29% of the dose was excreted in the urine and 38-45% in the feces over a 7-day period. In dogs, 39-74% of the administered dose was excreted in the urine and 26-43% in the feces over the same period. In both rats and dogs, bromperidol was extensively metabolized; most of the urinary radioactivity associated with metabolites arose from cleavage of the bromperidol molecule via oxidative N-dealkylation. After administration of 14C-bromperidol to human volunteers, 28-50% of the dose was eliminated in the urine while 18-46% was eliminated in the feces over a 13-day period. Although bromperidol appeared to be extensively metabolized in man, the major portion of the urinary radioactivity (70-75%) was associated with the O-glucuronide conjugate of intact drug. Thus, oxidative N-dealkylation does not appear to be the major urinary metabolic pathway of the drug in man.     

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.     

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)     

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.     

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%.