Disposition of [3H]fluvastatin following single oral doses in beagle dogs and rhesus monkeys with bile fistulae

The disposition of [³H]fluvastatin was examined following single oral doses in dogs (12.4 mg kg^?1) and monkeys (0.48 45.5 mg kg^?1) with bile fistulae. Serial plasma and complete urine, feces, and bile were collected at designated intervals for 3 or 4 d, and were analyzed for total radioactivity and unchanged fluvastatin. In the dog, peak radioactivity concentrations (C_max) averaged 7260 ng equiv. mL^?1 and the mean time to peak (t_max) was ～ 9 h. In the monkey, the mean radioactivity t_mzx values were ～ 5 and 13 h following the low and high doses, the respective C_max values being 116 and 10400 ng equiv. mL^?1. The mean AUC of total radioactivity was proportional to the dose while that of fluvastatin was overproportional to dose, suggesting dose indepedent absorption but saturable first-pass effect. The AUC ratio of unchanged fluvastatin versus total radioactivity was approximately 63% in the dog, and 9% and 13% for the low and high doses, respectively in the monkey. The bile was the major excretory route of radioactivity (dog, 56%; low-dose monkey, 73%; high-dose monkey, 69%) whereas the renal pathway accounted for < 5% of the dose in both species. Approximately 12% of the biliary radioactivity in the dog was due to intact fluvastatin, compared with 0% and 7.5% after the low and high doses in the monkey. These results showed a smaller extent of fluvastatin metabolism in the dog than in the monkey, and suggested that metabolism in the monkey was saturable in the dose range studied.     

Disposition of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)- 1H-indole-3-methanol (59-801), a hypoglycaemic agent in rats, dogs and monkeys

1. The disposition of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4 isoxazolyl)-1H-[3-14C]indole-3-methanol, an oral hypoglycaemic drug, has been studied in the rat, dog and monkey. 2. Oral doses of the drug were almost completely absorbed. The rate of absorption was rapid in the rat but less rapid in dog and monkey. Due to first-pass effect, the absolute bioavailability of the drug was incomplete and ranged from 60-75% in the monkey to 90% in the dog. 3. Intravenous as well as oral doses of the radiolabelled drug were rapidly and extensively distributed to body tissues. In rat, concentrations of radioactivity in all tissues except the brain exceeded, or were similar to, corresponding blood levels. Tissue and blood radioactivity levels were higher in female than in male rats, and increased disproportionately with increasing dose. 4. The drug was partially metabolized before excretion, the extent of metabolism ranging from ca. 50% in the rat to 90% in the monkey. Although only a limited number of animals were used, metabolism appeared to be saturable within the dose range studied in dog and monkey but not in rat. The half-life of unchanged drug was dose-independent in the rat (1.4 h), but tended to increase with increasing dose in the dog (4.1-7.2 h) and monkey (2.1-4.5 h). 5. In all three species, the administered radioactivity was recovered predominantly in urine, although biliary excretion also played an important role in drug elimination. Recovery of dose was essentially complete within 1-2 days.     

Disposition of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3- methanol (59–801), a hypoglycaemic agent,in rats,dogs and monkeys

1. The disposition of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1 H-[3-¹⁴C]indole-3-methanol, an oral hypoglycaemic drug, has been studied in the rat, dog and monkey.

2. Oral doses of the drug were almost completely absorbed. The rate of absorption was rapid in the rat but less rapid in dog and monkey. Due to first-pass effect, the absolute bioavailability of the drug was incomplete and ranged from 60–75% in the monkey to 90% in the dog.

3. Intravenous as well as oral doses of the radiolabelled drug were rapidly and extensively distributed to body tissues. In rat, concentrations of radioactivity in all tissues except the brain exceeded, or were similar to, corresponding blood levels. Tissue and blood radioactivity levels were higher in female than in male rats, and increased disproportionately with increasing dose.

4. The drug was partially metabolized before excretion, the extent of metabolism ranging from ca. 50% in the rat to 90% in the monkey. Although only a limited number of animals were used, metabolism appeared to be saturable within the dose range studied in dog and monkey but not in rat. The half-life of unchanged drug was dose-independent in the rat (1.4 h), but tended to increase with increasing dose in the dog (4.1–7.2 h) and monkey (2.1–4.5 h).

5. In all three species, the administered radioactivity was recovered predominantly in urine, although biliary excretion also played an important role in drug elimination. Recovery of dose was essentially complete within 1–2 days.     

Disposition and metabolism of benoxaprofen in laboratory animals and man.

1. The absorption, distribution, metabolism and excretion of benoxaprofen, a novel anti-inflammatory compound, has been studied in the dog, mouse, rat, rabbit, rhesus monkey and man. 2. Benoxaprofen was well absorbed after oral administration of doses of 1 to 10 mg/kg in all six species. Only unchanged drug was detected in plasma. It was extensively bound to plasma proteins, the highest binding occurring in man (99.8%) and rhesus monkey (99.6%). 3. Species differences were observed in the plasma elimination half-life, the longest being in man (33 h). The rat and mouse also had high values (28 and 24 h respectively) whereas in the other species, values were less than 13 h. 4. After an oral dose of [14C]benoxaprofen (20 mg/kg) to female rats, tissue concn. was highest in liver, kidney, lungs, adrenals and ovaries. Tissue distribution in the pregnant rat was identical to the normal female. The compound was found in the foetus but at a concn. lower than in all maternal organs. 5. There was a marked species difference in the route of excretion. In man, rhesus monkey and rabbit, excretion in the urine was a major route, whilst biliary--faecal excretion was the only effective route in the rat and dog. 6. No major metabolic transformation of benoxaprofen was observed. Man and dog excreted the compound predominantly as the ester glucuronide whereas the rat, mouse, rabbit and rhesus monkey excreted a large proportion of the dose unchanged.     

Comparison of celecoxib metabolism and excretion in mouse,rabbit, dog,cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit,the EM(extensive) and PM(poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [¹⁴C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [¹⁴C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.     

Comparison of celecoxib metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.     

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%.     

Comparative biodisposition and metabolism of 14C-(+/-)-fenfluramine in mouse, rat, dog and man.

1. The comparative metabolism of fenfluramine was investigated in mouse, rat, dog and man following a single oral dose of 14C-(+/-)-fenfluramine hydrochloride (1 mg/kg), and also in rat after eight consecutive 12-h subcutaneous doses (24 mg/kg). 2. Main route of excretion of radioactivity in all species and at all doses was into urine (> 80%), with only minor amounts of radioactivity found in faeces. 3. From all species examined a total of 11 metabolites were observed in urine and plasma by t.l.c. and h.p.l.c. analysis and no metabolite was present in the plasma which was not present in urine. 4. All species dealkylate fenfluramine to the active metabolite norfenfluramine, to a relative greater or lesser extent, with plasma metabolic ratios (norfenfluramine/fenfluramine) showing inter-animal variation (rat > dog > mouse = man). 5. These differences are due to the efficient deamination of both compounds to polar inactive metabolites in man, with less dealkylation and lower plasma levels of norfenfluramine compared with the other species studied. 6. In conclusion, major species differences in the metabolism of (+/-)-fenfluramine, both qualitative and quantitative were observed, and no one species had a similar metabolic profile to that found in man.     

Excretion and metabolism of recainam, a new anti-arrhythmic drug, in laboratory animals and humans

The metabolic disposition of recainam, an antiarrhythmic drug, was compared in mice, rats, dogs, rhesus monkeys, and humans. Following oral administration of [14C]recainam-HCl, radioactivity was excreted predominantly in the urine of all species except the rat. Metabolite profiles were determined in excreta by HPLC comparisons with synthetic standards. In rodents and rhesus monkeys, urinary excretion of unchanged recainam accounted for 23-36% of the iv dose and 3-7% of the oral dose. Aside from quantitative differences attributable to presystemic biotransformation, metabolite profiles were qualitatively similar following oral or iv administration to rodents and rhesus monkeys. Recainam was extensively metabolized in all species except humans. In human subjects, 84% of the urinary radioactivity corresponded to parent drug. The major metabolites in mouse and rat urine and rat feces were m- and p-hydroxyrecainam. Desisopropylrecainam and dimethylphenylaminocarboxylamino propionic acid were the predominant metabolites in dog and rhesus monkey urine. Small amounts of desisopropylrecainam and p-hydroxyrecainam were excreted in human urine. Selective enzymatic hydrolysis revealed that the hydroxylated metabolites were conjugated to varying degrees among species. Conjugated metabolites were not present in rat urine or feces, while conjugates were detected in mouse, dog, and monkey urine. Structural confirmation of the dog urinary metabolites was accomplished by mass spectral analysis. The low extent of metabolism of recainam in humans suggests that there will not be wide variations between dose and plasma concentrations.     

Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys

DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, especially to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biological half-life and slow elimination of radioactivity were distinctive in particular, compared with commercial taxanes. DJ-927 (as parent compound and its metabolites) is widely distributed to tissues except the brain. These preclinical data are useful for the design of clinical trials of DJ-927 and also for their interpretation.     

Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers.

The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single-dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple-dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (greater than 90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2- and 10-mg doses was only 19 to 29% because of extensive first-pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2- to 10-mg dose range, as indicated by dose-proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half-lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40-mg doses of [3H]fluvastatin resulted in no time-related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first-pass effect on fluvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolism of l-N-benzyl- -methoxy-3-trifluoromethylphenethylamine hydrochloride in the rat, dog, monkey and man

l-N-benzyl-β-methoxy-3-trifluoromethylphenethylamine hydrochloride, an anorectic agent, was administered to rats, dogs, monkeys and man, employing either the ¹⁴C labeled or nonistopic drug. The compound was essentially completely absorbed. A major portion of the dose was excreted during the first 24 hr; however, drug-related material continued to be slowly excreted over a 96-hr collection period.

Urinary excretion of drug-related material, as compared to fecal excretion, was slightly lower in the rat and approximately twice as high in the dog. Urinary excretion in the monkey was in the same range as seen in the dog. Human urinary excretion of dose was comparable to that of the rat. Fecal excretion was not measured in the latter two species. Rat biliary excretion of over 50 % of dose in 24 hr showed the bile to be an important excretion route in this species. Plasma levels of drug-related material were prolonged in all species studied. These levels, when measured in monkeys, remained relatively constant during a 24-hr sampling period. The remaining three species showed plasma parent compound half-lives of approximately 3–4 hr. The desbenzyl metabolite and total drug-related material half-lives were in the range of 7–9 hr.

Drug distribution in tissues was highest in concentration in the vascular organs i.e. liver, lungs, kidneys and spleen. Brain tissue in rats contained only basic drug-related material which was predominantly the desbenzyl metabolite. Only a trace of unchanged parent compound was present. Metabolites, identified by a combination of thin-layer and gas chromatography, by mass spectral and isotope dilution analyses, were trifluoromethyl-O-methylphenethylamine, trifluoromethyl-O-methylmandelic acid, trifluoromethylmandelic acid and trifluoromethylhippuric acid. Conjugation of the desbenzyl metabolite as a glucuronide was found in dog and monkey, indicated in man, but not found in the rat.

Assay methods specific for the drug and the desbenzyl metabolite (gas chromatography) and a nonspecific method which measured the organically bound fluorine of the compound were developed and applied to plasma and urine specimens.     

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)     

Metabolism of amlodipine in the rat and the dog: a species difference

1. Following oral and i.v. doses of 14C-amlodipine to rat and dog, 40-50% of the dose was excreted in the urine indicating that the oral dose was well absorbed. Urinary and faecal excretion in rat was essentially complete within 48 h but was prolonged during 168 h in dog. 2. Metabolite patterns were dissimilar for rat and dog for both urine and faeces. The majority (about 95%) of the urinary metabolites were identified for both species; unchanged drug accounted for 10% and 2% of the urinary radioactivity in rat and dog respectively. 3. In rat, the principal route of metabolism involved cleavage of the 5-methoxy-carbonyl group of both the parent dihydropyridine and its pyridine analogue. In contrast, metabolism in dog involved oxidative deamination of the 2-aminoethoxy-methyl side-chain. 4. Secondary metabolism in both rat and dog was similar to that of other calcium channel blockers of the dihydropyridine class, with oxidation to the pyridine form being followed by aliphatic hydroxylation in the 6-position or O-dealkylation in the 2-position and lactonization.     

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.     

Disposition of orally and intravenously administered methyltetrahydrofuran in rats and mice

The disposition of [14C]methyltetrahydrofuran (14C-MTHF) in rats and mice was determined by following changes in the radioactivity in tissue and excreta with time after dosing. MTHF administered orally (1, 10, or 100 mg/kg) or intravenously (1 mg/kg) to either rats or mice was rapidly metabolized and excreted with <8% (mice) or 8-22% (rats) of the dose remaining in the body after 24 h (1 and 10 mg/kg doses) or 72 h (100 mg/kg dose). Based on recovery of radioactivity in excreta (other than feces) and tissues (other than the gastrointestinal [GI] tract), absorption of orally administered MTHF was essentially complete (93-100%). There were no overt signs of toxicity observed at any dose studied. The major route of excretion in mice was in urine followed by exhaled CO2. In rats the major route of excretion was exhaled CO2 followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose-dependent in both species; at lower doses exhaled VOC represented 1-5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOCs exhaled at the high dose indicated that the increase was due to exhalation of the parent compound, 14C-MTHF. Analysis of urine showed three highly polar peaks in the mouse urine and two polar peaks in the rat urine. Because the 14C label in MTHF was in the methyl group, the polar metabolites were considered likely due to the one-carbon unit getting into the metabolic pool and labeling intermediate dietary metabolites.     

Metabolic disposition and pharmacokinetics of pelrinone, a new cardiotonic drug, in laboratory animals and man

The metabolic disposition of pelrinone, a cardiotonic drug, was studied in mouse, rat, rabbit, dog, monkey and man. Pelrinone was rapidly and extensively absorbed in rodents, dogs, monkeys and man. Except in rabbits, the major portion of the serum radioactivity was due to parent drug. Pelrinone was moderately bound to human serum proteins and weakly bound to serum proteins from animals. Radioactive compounds were rapidly eliminated from rat tissues with the highest concentrations found in organs associated with absorption and elimination. After a 1.0 mg/kg i.v. dose, the rapid elimination of pelrinone from mouse, rat and dog serum precluded estimation of an elimination half life (t1/2). However, after higher oral or i.v. doses, a more prolonged elimination phase was apparent and the t1/2 of pelrinone ranged from 8-10 h in rodents and dogs. In human subjects given escalating oral or i.v. doses of pelrinone, the elimination t1/2 was independent of dose and averaged 1-2 h. The serum AUC of pelrinone was linearly dose-related following oral doses up to 20 mg/kg in dogs and 100 mg in man. In mice, a greater proportional increase in AUC occurred between oral doses of 2-100 mg/kg while in rats, the serum AUC increased in less than proportional manner from 10-200 mg/kg p.o. In all species, radioactive compounds were excreted mainly in the urine. No metabolites were detected in dog and human urine while small amounts of unconjugated metabolites were excreted in mouse and rat urine.     

Pharmacokinetics,metabolism and pharmacodynamic s of a benzimidazole angiotensin II type 1 receptor antagonist in the beagle dog and cynomologus monkey

1. The pharmacokinetic s and disposition of E4177, an angiotensin II (Ang II) type 1 receptor antagonist, were studied in the beagle dog and cynomologus monkey following intravenous (i.v.) and oral (p.o.) administration. The relationship between the plasma concentrations of E4177 and Ang II receptor blockade were investigated in both species.

2. Single 0.3?mg kg i.v. doses of E4177 in dog and monkey were eliminated rapidly. The elimination half-lives were 1.9 and 2.0 h, and the systematic plasma clearance values were 9.1 and 12.9 ml/min/kg respectively.

3. The oral bioavailabilityof single doses of 0.3-3?mg/kg of E4177 was > 60% in both dog and monkey. The absorption by both species was rapid, with peak plasma levels observed within 1 h, and the areas under the concentration versus time curve to infinity were proportional to the dose.

4. The apparent volumes of distributionat the steady-state were 1.0 and 1.2 l/kg in dog and monkey respectively. Tissue penetration was probably limited by the relatively high binding to plasma proteins (approximately 92.0 and 98.6% in the dog and monkey respectively).

5. Faecal excretion was the major eliminationpathway for radioactivity(approximately 90% of the dose) in both species after 1?mg/kg p.o. administration of ¹⁴C-E4177. Unchanged E4177 was the major radioactive component in the urine and faeces (0-24 h) of both species, accounting for approximately 85% of dose. In monkey, a minor metabolitein excreta and plasma was identified as the phase I metabolite M1, which is produced from E4177 by methyl- hydroxylation. M1 was not detected in dog. 6. The unbound plasma concentration versus blockade of the exogenous Ang IIinduced vasopressor response was also determined after an i.v. administrationof E4177 to dog and monkey. The relationship between the unbound E4177 concentration and the effect was highly significant in both species. The IC₅₀ of the dog and monkey were not significantly different: 2.6 and 2.7 ng/ml respectively.     

The disposition and metabolism of flurbiprofen in several species including man.

Flurbiprofen was rapidly absorbed in all species studied. 2. Half-lives of elimination measured 0 to 12 h after a single dose were: mouse 3.4 h, rat 2.5 h, dog 10.1 h, baboon 3.1 h and man 3.9 h. A second phase of elimination was seen in the dog. Flurbiprofen accumulated in the circulation of the dog on repeated dosing. 3. After dosing with [14C]flurbiprofen, tissue levels of radioactivity in dog and baboon were similar to that in plasma. In the rat, levels were slightly elevated in liver, kidney, large intestine and thyroid after repeated dosing. 4. The dog excreted equal amounts of radioactivity in urine and faeces. In other species renal excretion was the more important route. 5. Six metabolites have been detected, the most important being: 2-(2-fluoro-4'-hydroxy-4-biphenylyl)propionic acid (metabolite 1), 2-(i-fluoro-3',4'-dihydroxy-4-biphenylyl)propionic acid (metabolite 2) and 2-(2-fluoro-3'-hydroxy-4'-methoxy-4-biphenylyl)propionic acid (metabolite 3). The proportions of the metabolites and the extents of their conjugation varied among the species. 6. Metabolites were detected in the circulation of rat, mouse and baboon but not in dog and man. 7. Flurbiprofen did not affect the hepatic drug-metabolizing enzyme system of rat. 8. Flurbiprofen was extensively bound to serum protein of rat, dog, baboon and man.     

Disposition and metabolism of timiperone in the rat, dog, and monkey

The disposition and metabolism of timiperone (TP), a new butyrophenone antipsychotic, were studied in the rat, dog, and monkey given [14C]TP orally at different dose levels. [14C]TP was absorbed by the three species; the elimination of radioactivity from the blood was most rapid in the rat, and slowest in the dog. In the rat, blood and tissue concentrations of radioactivity were dose-dependent, and persisted after low and high doses. Tissue/blood ratios of radioactivity concentration in most of the rat tissues were much larger than 1.0, indicating that TP has a high affinity for the tissues. Approximately 19, 36, and 54% of the administered dose were excreted into dog, rat, and monkey urine, respectively, within 3 days, and the residue into the feces. [14C]TP was metabolized by N-dealkylation and the reduction of the butyrophenone sidechain to form 4-[4-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]-1-(4-fluorpheny l)-1-butanol (M-II), 2,3-dihydro-1-(4-piperidinyl)-2-thioxo-1H-benzimidazole (M-V), and N-(4-fluorophenylacetyl)glycine (M-b-l). Urinary major metabolites in all the species were M-V and M-b-l. Metabolite patterns in the rat brain indicated that unchanged TP accounted for the major part of total radioactivity. Similar patterns were obtained in rat and dog plasma, but not in monkey plasma.