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 Fate of the Coronary Dilator 4-(3,4,5-Trimethoxycinnamoyl)-1-(N-Isopropylcarbamoylmethyl)- Piperazine in the Rat,Dog and Man

1. An oral dose of the coronary dilator 4-(3,4,5-trimethoxycinnamoyl)-1- (N-isopropylcarbamoylmethyl)-piperazine was readily absorbed and more than 75% of the dose was excreted within 24 h by the rat, dog and man. In 4 days, rat, dog and man excreted in the urine and faeces respectively 32.5 and 62.3%, 43.9 and 49.1%, and 57.8 and 43.3%. Faecal radioactivity was mainly excreted via the bile.

2. Plasma concentrations of radioactivity reached a maximum within 1 h in rats and dogs and within 2 h in man. For several h, more than 50% of the radioactivity circulating in the plasma of rats and more than 80% in man was due to unchanged drug.

3. Sequential whole-body autoradiography of the rat indicated that much of the radioactivity was distributed in the liver, kidneys and gastrointestinal tract and that there was significant uptake into the heart and lungs.

4. Although similar metabolites were excreted by the rat, dog and man, the relative proportions differed. 11.7, 2.3 and 28.8% respectively of the unchanged drug were excreted in the urine and 13.1, 19.5 and 10.4% respectively of the principal metabolite a glucuronide whose exact structure was not determined. Other metabolites included 4-(3,4,5-trimethoxycinnamoyl)-1-carbamoylmethyl piperazine and N-(3,4,5-trimethoxycinnamoyl)-piperazine.     

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.     

Pharmacokinetics, enterohepatic circulation and biotransformation of [2-3H]-9,9-Dimethylacridane-10-carboxylic acid S-(2-dimethylamino) thiolethyl ester in the rat and dog

Dogs receiving a 7.5 mg/kg oral or i.v. dose of tritium labelled 9,9-dimethylacridane-10-carboxylic acid S-(2-dimethylamino)thiolethyl ester (DMA) as the methane sulfonate salt (DMA-MS) excreted 86-95% of the radioactivity within 6 days. A similar recovery was obtained for rats receiving 300 mg/kg orally of 15 mg/kg i.v. In both species, approximately 66% of the dose was excreted in the feces as metabolites. Absorption of the oral dose was shown to be 80% and 100% for the rat and dog, respectively. Up to 47% of an i.v. dose was excreted in the bile of rats and an efficient enterohepatic circulation process insues. The parent drug is rapidly metabolized in the tissues yielding at least 6 polar metabolites which contribute to relatively long plasma half-lives in the order of 40 h for dogs and 58-90 h for rats. An atypical increase in plasma radioactivity following an i.v. dose could be rationalized in view of these results. Metabolite profiles were examined in plasma, urine, bile and feces and found to be qualitatively similar. Des-methyl-DMA and DMA-N-oxide were identified as two minor metabolites.     

Absorption, metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog

1. The oral no overall adverse effect level (NOAEL) for chronic toxicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat is approximately 1.3 mg kg(-1) and in dog is 0.2 mg kg(-1). In an attempt to explain the difference in toxicology between these species, rats and dogs were orally dosed with (14C)-MCPA at 5 or 100 mgkg(-1) and plasma toxicokinetics, rates and routes of excretion and biotransformation were investigated. 2. Elimination of radioactivity in rat plasma was biphasic and in dog was monophasic. Rat eliminated radioactivity from plasma significantly faster than dog (approximate values biased on total radioactivity: 5 mg kg(-1) rat: t 1/2 dist 3.5 h, t 1/2 elim 17.2-36.2 h, AUC(0-infinity) 230 microg equiv hg(-1); 5 mg kg(-1) dog: t 1/2 47h, AUC(0-infinity) 2,500 microg equiv h g(-1); 100 mg kg(-1) rat: t 1/2 dist 10h, t 1/2 elim 10.27-25.4h, AUC(0-infinity) 5,400 microg equiv hg(-1); l00 mg kg(-1) dog: t 1/2 h, AUC(0-infinity) 20,500 microg eqiv h g(-1). 3. For both species, the principal route of excretion was in urine but renal elimination was notably more rapid and more extensive in rat. 4. In both rat and dog, excretion of radioactivity was mainly as MCPA and its hydroxylated metabolite hydroxymethylphenoxyacetic acid (HMCPA). In rat, both were mainly excreted as the free acids although a small proportion was conjugated. In dog, the proportion of HMCPA was increased and the majority of both species was excreted as glycine or taurine conjugates. 5. These data, along with previously published accounts, indicate that renal elimination of MCPA in dog is substantially slower than in rat resulting in disproportionate elevation of AUC (based on total radioactivity) in dog compared with rat.     

Metabolism of 8-(methylthio)cyclic 3',5'-adenosine monophosphate by rats and dogs after oral or intravenous dosing and in vitro by subcellular preparations of dog liver.

8-(Methylthio-14C or -35S)cyclic 3',5'-adenosine monophosphate (I) was given intravenously to rats (5 mg/kg) and orally and intravenously to dogs (0.25, 2.5, or 50 mg/kg). Oral doses were absorbed well but slowly. Plasma half-lives in dogs were about 3 hr after oral or intravenous doses of 0.25 or 2.5 mg/kg and ranged from 5 to 12 hr after oral or intravenous doseas of 50 mg/kg. Plasma glucose and insulin concentrations in dogs were increased by oral or intravenous doses of the compound. Regardless of the route, excretion of radioactivity by rats and dogs at all doses was chiefly in the urine (74-87% of the dose); the remainder was excreted in the feces or bile. Compound I was rapidly distributed to most tissues of dogs but entered the brain and certain portions of the eye slowly and to a limited extent. Urine and plasma of dogs and urine of rats contained I, 8-(methylthio)adenosine, and at least two other unidentified metabolites. Compound I and cyclic 3',5'-adenosine monophosphate were metabolized in vitro by the soluble fraction of dog liver to form 8-(methylthio)adenosine-5'-monophosphate and adenosine-5'-monophosphate, respectively. These compounds were further converted to 8-(methylthio)adenosine and adenosine, respectively. Compound I was metabolized in vitro more slowly than cyclic 3',5'-adenosine monophosphate.     

The disposition and metabolism of 5-(4,5-dihydro-2-phenylbenz[e]indol-3-yl)salicylic acid (fendosal) in the rat, mouse, rabbit, do, rhesus monkey, and man

The disposition and metabolism of 5-(4,5-dihydro-2-phenylbenz[e]indol-3-yl)salicylic acid (fendosal) a new salicylate-type analgesic, has been studied in the rat, mouse, rabbit, dog, rhesus monkey, and man. Animals were given single oral or parenteral doses at levels of 5, 10, or 50 mg/kg; human volunteers received 200 mg orally. In all species, virtually all radioactivity was excreted in the feces. Biliary excretion accounted for approximately 50% of an oral dose in the rat and dog. Enterohepatic circulation was demonstrated in the rat. The compound was fairly rapidly absorbed in all species except the rhesus monkey. The principal excretion products found in all species were unchanged fendosal and a monohydroxylated metabolite, the latter being present both in the free state and as a glucuronide. A minor metabolite, present only in man and rhesus monkey, was tentatively identified as a dihydroxylated metabolite. These compounds were, however, detected only in unpurified samples. During the isolation and purification procedure, oxidation occurred, resulting in the production of the corresponding dehydrogenated derivatives, which were the actual materials whose structures were elucidated.     

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%.     

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.     

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor, in dogs: identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5 mg kg(-1) dose of [(14)C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72 h. Male bile duct-cannulated dogs excreted a mean of approximately 56% of the dose in bile, approximately 11% in feces, and approximately 25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [(14)C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.     

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.     

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)     

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor,in dogs: Identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5?mg?kg^?1 dose of [¹⁴C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72?h. Male bile duct-cannulated dogs excreted a mean of ～56% of the dose in bile, ～11% in feces, and ～25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [¹⁴C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.     

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).     

Metabolism of (14C)-quazodine in the rat, dog, and man.

The pharmacokinetics of [¹⁴C]-quazodine, a new bronchodilator, were examined in man and dog. Absorption, metabolism, and excretion of quazodine were studied in the rat, dog, and man, while distribution of the drug was measured in rats. After iv dosage, clearance of unchanged drug from plasma was rapid in both dogs and man and followed a biexponential decay curve in accordance with the equation C_p = Ae^?αt + Be^?βt. A good fit between the actual data and the computer-generated curves was obtained employing a nonlinear regression analysis computer program. After po administration quazodine was rapidly absorbed in both man and dog, a peak plasma concentration being observed at 0.5 hr in man and at 1 hr in dogs. The drug did not localize in cerebrospinal fluid of dogs. Radioactivity was found in all tissues of rats at 1 hr after oral dosage, and no evidence for extreme drug localization or prolonged retention was found in any tissue including brain. In rats, 71.9% of the dose was recovered in urine and 14.2% in feces during the first 3 days after dosing. The 72-hr recoveries in dog urine and feces were 61.4 and 25.8%, whereas in humans these values were 84.1 and 1.1%, respectively. The major pathway for metabolism of quazodine in man, and to a lesser extent in the dog and rat, was by demethylation at the 7-position of the quinazoline ring-system followed by conjugation with glucuronic acid or sulfate. The glucuronide conjugate accounted for 78.0% of the radioactivity in human urine, 45.1% in dog, and 27.4% in rat urine. The amount of radioactivity present as the sulfate conjugate was 3.1, 15.3, and 10.5% in human, dog, and rat urine, respectively.     

Pharmacokinetics and metabolism of a leukotriene D4/E4-antagonist (2-[3'-(2"-quinolylmethoxy)phenylamino]benzoic acid) in rat, dog,guinea pig and man

1. The absorption, distribution, metabolism and excretion of 2-[3'-(2"-quinolyl-methoxy)phenylamino]benzoic acid (QMPB), a novel leukotriene D4/E4 antagonist, were investigated in rat, dog, guinea pig and man. 2. The oral absorption of the potassium salt of QMPB was rapid and almost complete (90%) in rats, and about 50% in dogs. In man, high oral bioavailability was indicated. Absorption in dogs of the zwitterion form was only 7%. 3. The distribution of 3H-QMPB was examined in rats and guinea pigs. Whole-body autoradiography in rats showed that radioactivity was concentrated predominantly in the liver, bile and intestinal lumen, after both oral and i.v. administration. 4. A major metabolite was identified as the O-ester beta-glucuronide of QMPB. 5. Renal excretion in rat, dog and man was very low. In rat, almost complete biliary excretion of QMPB as the glucuronide conjugate was demonstrated. 6. Pronounced enterohepatic circulation of QMPB was demonstrated in rats, and the plasma concentration curves and the negligible renal excretion in dog and man also indicate enterohepatic circulation in these species.     

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.     

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 physiological disposition of the anti-tussive agent, 1,2,3,4a,9b-hexahydro-8,9b-dimethyl-4-[3-(4-methylpiperazin-1-yl)propionamido]dibenzofuran-3-one dihydrochloride Azipranone, in man, rat, dog and baboon.

1. The absorption, tissue distrigution, elimination and biotransformation of the anti-tussive agent Azipranone labelled with 14C have been investigated after oral dosing to rat, dog, baboon and man and parenteral administration to rat and baboon. 2. Levels of radioactivity in plasma were maximal within 20 min of dosing in the rat and after 1-2 h in the remaining species. The concn. declined thereafter with a half-life estimated at 1, 3-4 and 18-24 h for rat, dog, and baboon and man respectively. 3. Three human volunteers excreted 53, 62 and 70% of the radioactivity in the urine in 96 h while the remaining species excreted 50-70% of the dose in the faeces in the same period. 4. Radioactivity was rapidly and extensively eliminated in the bile of both rat and baboon after administration of [14C]Azipranone. 5. The 24 h urine samples from all species contained ten major and a similar number of minor radioactive components. 6. In hepatic microsomal preparations, biotransformations of Azipranone are catalysed by enzymes requiring both NADPH2 and cytochrome-P450.     

Disposition and metabolism of 2-(2'(1',3'-dioxolan-2-yl)-2- methyl-4-(2'-oxopyrrolidin-1-Yl)-6-nitro-2h-1-benzopyran (SKP-450) in rats.

The disposition and metabolism of the new antihypertensive agent 2-(2"(1", 3"-dioxolan-2-yl)-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-nitro -2H-1-benzopyran (SKP-450) were investigated in male rats after single oral and i.v. doses of 14C-labeled compound. After an oral 2.0 mg/kg dose, mean radiocarbon recovery was 98.2 +/- 2.3% with 31.1 +/- 7.3% in the feces and 67.1 +/- 14.3% in the urine. Biliary excretion of radioactivity for the first 24-h period was approximately 40%, suggesting that SKP-450 is cleared either by hepatobiliary excretion or by renal excretion. SKP-450 was well absorbed; bioavailability calculated on the basis of radioactivity was 68 to 97%. Tissue distribution of the radioactivity was widespread with high concentrations in the liver and kidney but low central nervous system penetration. Radio-HPLC analysis of bile and urine from rats indicated the extensive metabolism of SKP-450 into oxidative metabolites. Oxidative metabolism of the dioxolanyl ring resulted in an aldehyde intermediate, subsequently confirmed in vitro, which was further oxidized to the corresponding carboxylic acid (M1) or reduced to the corresponding alcohol (M3). No parent drug was detected in the urine or bile. Glucuronide conjugate of M3 was also detected in urine and bile, accounting for 5.8 +/- 2.1 and 8.9 +/- 3. 7% of the excreted radioactivity, respectively. Quantitative data obtained from plasma samples suggest that the majority of circulating radioactivity was associated with metabolites. Our results suggest that the long duration of pharmacological activity of SKP-450 (>10 h) is largely attributable to its metabolites.