2,3,6,2′,3′,6′-Hexachlorobiphenyl: Distribution,metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 2,3,6,2′,3′,6′-hexachlorobiphenyl (236-HCB) were investigated in beagle dogs and cynomolgus monkeys (Macaca fascicularis). Following a single iv dose of [¹⁴C]236-HCB (0.6 mg/kg) excreta, blood, and tissues were collected at time intervals ranging from 15 min to 15 days for determination of levels of parent compound and its metabolites. Elimination of the parent PCB in the blood of both species was biphasic with a terminal-phase elimination rate constant of 0.23 day^?1 for the dog and 0.15 day^?1 for the monkey. By 24 hr the dog excreted 52% of the dose; 41% in the feces; 11% in the urine. The percentage dose remaining was found largely in liver, muscle, fat, and skin. By 3 days 70% of the dose was excreted. During the first 24 hr the monkey excreted 19% of the dose with about equal amounts appearing in urine and feces. The percentage dose remaining in the body was localized as parent compound in fat (15%) with lesser amounts in skin, muscle, and liver. By 15 days 61% of the dose was excreted, primarily in the feces. In anesthetized dogs 26% of the dose was excreted into the bile within 2 hr, while anesthetized monkeys excreted only 2.4% of the dose by that route. The data present a clear species variation between the dog and the monkey in the rate of metabolism of 236-HCB and its subsequent excretion via the bile.     

4,4′-Dichlorobiphenyl: Distribution,metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 4,4′-dichlorobiphenyl (4,4′-DCB) were investigated in beagle dogs and cynomolgus monkeys (Macaca fascicularis). Following a single iv dose of [¹⁴C]4,4′-DCB (0.6 mg/kg) excreta, blood, and tissues were collected at time intervals ranging from 15 min to 28 days for determination of levels of parent compound and its metabolites. Elimination of the parent PCB in the blood of both species was biphasic with a terminal-phase elimination rate constant of 0.018 hr^?1 for the dog and 0.002 hr^?1 for the monkey. By 24 hr the dog excreted 50% of the dose in the feces (43%) and the urine (7%). The percentage dose remaining was found largely as parent compound in the fat with some in muscle and skin. By 5 days 90% of the dose was excreted. In contrast, during the first 24 hr the monkey excreted less than 15% of the dose with less than 1% in the feces. The percentage dose remaining in the body was localized as parent compound in fat (33%) with lesser amounts in skin and muscle. By 28 days 59% of the dose was excreted, primarily in the urine. In anesthetized dogs 33% of the dose was excreted into the bile within 2 hr, while the monkey excreted only 0.4% of the dose by that route. The data present a clear species variation between the dog and the monkey in both the rate and route of excretion of 4,4′-DCB.     

Metabolism and disposition of sulfinalol in laboratory animals

Peak levels of radioactivity in blood occurred 1.0 hr after oral administration of 3H-sulfinalol hydrochloride to rats, dogs, and monkeys. The plasma decay curve for intact sulfinalol in the dog was biphasic, with apparent first-order half-lives of 0.55 and 6.2 hr. Rats excreted 42.5% of the dose in the urine and 31.8% in the feces after 24 hr. Urinary and fecal recovery were 53.8% and 41.2%, respectively, after 10 days for dogs and 57.8% and 38.0%, respectively, after 9 days for monkeys. Free sulfinalol (11.8% of the dose) was the major component in dog feces with lesser amounts of the sulfide and sulfone metabolites, also in the unconjugated form. All metabolites in dog urine were conjugated with glucuronic acid, with sulfinalol (28.5%) and desmethylsulfinalol (8.5%) representing the major constituents, whereas the sulfone and sulfide metabolites were minor ones. Monkey feces contained primarily unconjugated forms of the desmethyl sulfide metabolite (17.0%) and sulfinalol (7.5%); lesser amounts of desmethylsulfinalol and the sulfone metabolite were present. Desmethylsulfinalol (8.7%) and its sulfate (7.0%) and glucuronide (4.0%) conjugates were the major urinary metabolites in the monkey; sulfinalol (1.4%), its glucuronide conjugate (5.1%), the desmethyl sulfide metabolite (and its sulfate conjugate), and the sulfone metabolite were also present.     

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.     

Disposition and metabolism of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine in rats, dogs, and monkeys

The disposition and metabolism of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a new agent with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties, was studied in rats, dogs, and rhesus monkeys. [3H]benzene-MK-801 was administered orally at a dose of 1 mg/kg. MK-801 was measured in plasma by GLC using a nitrogen detector; the overall sensitivity of the method was 3 ng/ml. Radioactivity was excreted mainly in urine of dogs and monkeys but fecal excretion in rats was also extensive. The apparent plasma t1/2 of MK-801 in the rat and dog was approximately 1 hr. Maximal plasma levels of MK-801 in the rat, dog, and monkey were 46 (0.5 hr), 16 (0.25 hr), and 10 (2 hr) ng/ml, respectively. Radioactivity was extensively excreted in rat bile and was widely distributed among various tissues. Major metabolites of the drug in rat and dog urine were the 2- and 8-hydroxy analogs (rat) and the N-hydroxy derivative (dog).     

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.     

Extensive Biliary Excretion of the Sulfasalazine Analogue,Susalimod, but Different Concentrations in the Bile Duct in Various Animal Species Correlating to Species-Specific Hepatobiliary Toxicity

Abstract: Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses ≥75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, ≥90%, mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 μmol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were ≤7000 μmol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (Påhlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.     

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.     

Extensive biliary excretion of the sulfasalazine analogue, susalimod, but different concentrations in the bile duct in various animal species correlating to species-specific hepatobiliary toxicity.

Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses > or =75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, > or =90%, mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 micromol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were < or =7000 micromol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (P?hlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.     

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.     

Comparative metabolism of 1,2,4-trichlorobenzene in the rat and rhesus monkey

1,2,4-Trichloro[14C]benzene (TCB) was administered po (10 mg/kg) and iv (10 mg/kg) to rats and rhesus monkeys. Urine was collected at 24 hr and the major urinary metabolites were quantified and identified. By 24 hr, the monkey had excreted 22% of the iv dose and roughly 40% of the po dose in the urine. Less than 1% of the radioactivity was found in the monkey's feces. An isomeric pair of 3,4,6-trichloro-3,5-cyclohexadiene-1,2-diol glucuronides accounted for between 48 and 61% of the urinary metabolites. Glucuronides of 2,4,5- and 2,3,5-trichlorophenol (TCP) accounted for 14 to 37%, and unconjugated TCP's accounted for 1-37% of the monkey's urinary metabolites. For the rat, 84% of the po dose and 78% of the iv dose were collected in the urine by 24 hr; 11% and 7%, respectively, were the amounts collected in the feces. Two isomers, 2,4,5- and 2,3,5-, of N-acetyl-S-(trichlorophenyl)-L-cysteine accounted for 60-62% of the rat's urinary metabolites. Free 2,4,5- and 2,3,5-isomers of trichlorothiophenol amounted to 33% of the urinary metabolites in the po dosed rats and 28% in the iv dosed rats; free 2,4,5- and 2,3,5-TCP's amounted to 1% and 10%, respectively. These results show that there is a sharp division in the types of conjugates formed in the metabolism of 1,2,4-TCB by the rat and rhesus monkey.     

Distribution and excretion of 2,3,6,2′,3′,6′- and 2,4,5,2′,4′,5′-hexachlorobiphenyl in senescent rats

The disposition of two symmetrical [¹⁴C]hexachlorobiphenyls (HCBs), 2,3,6,2′,3′,6′-HCB (236) and 2,4,5,2′,4′,5′-HCB (245), was studied in 24-month-old male Sprague-Dawley rats after iv treatment. Because body composition changes with age, complete dissections were performed on all rats to determine the size of the skin and adipose tissue depots. More than 50% of 236 was metabolized and excreted via the bile into the feces within 2 days. In contrast, 245 redistributed from the liver, muscle, and skin to adipose tissue where it accumulated without being metabolized. Only 2% of the total dose of 245 was excreted primarily in the feces within 21 days. The data obtained in this study were compared to results previously obtained from 2- to 3-month-old rats in this laboratory (Matthews and Tuey, 1980, Toxicol. Appl. Pharmacol.53, 377–388). Although the general pattern of HCB disposition did not change with age, i.e., metabolism and excretion of 236 versus persistence of 245, there were differences in the rates of elimination and in the tissue levels. There was enhanced metabolite retention in the muscle, skin, and adipose tissue of older animals which suggested an age-related decrease in tissue clearance. The large volume of adipose tissue in these older Sprague-Dawley rats could in part explain this observation. In general, there were few changes in decay rates from tissues or in biliary excretion. Age had a greater effect on the disposition of the persistent 245 than on the metabolizable 236. Thus, changes in body composition seemed to play a major role in age-related changes in the distribution and excretion of polychlorinated biphenyls.     

Nitrilotriacetate (NTA): human metabolism and its importance in the total safety evaluation program

Ten milligrams [¹⁴C]NTA in gelatin capsules was given (po) to 8 male subjects. Blood samples were taken, and samples of urine and feces were collected. In addition, expired CO₂ was collected in 4 of the subjects. NTA is poorly absorbed since approximately 12% of the dose appeared in the urine. The compound is rapidly excreted in the urine since 87% of the absorbed dose was excreted within the first 24 hr post dosing. The blood concentration peak occurred 1–2 hr after dosing. Reverse isotope dilution and thin-layer chromatography showed the urinary radioactivity to be unchanged NTA, and therefore no biotransformation had occurred. These results closely resemble the rat and dog metabolic data except that rats and dogs absorb 4 times more NTA than humans. The metabolic similarities among rats, dogs and humans lends some confidence to the extrapolation of the results derived from rat and dog toxicity tests for the purpose of estimating human safety.     

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 and metabolism of a new benzothiophene antiestrogen in rats,dogs and monkeys

1. A new benzothiophene-derived antiestrogen (LY156758) when orally administered was well absorbed in rats and monkeys while approx. 20% was absorbed in dogs.

2. In the rat the compound was subject to first-pass hepatic metabolism which led to low levels of parent drug in the systematic circulation together with a small amount as the glucuronide conjugate.

3. In monkeys the compound occurred primarily as the glucuronide conjugate of parent drug with very little circulating free drug.

4. The systemic bioavailability of free parent drug in plasma was 39% in rats, 17% in dogs and 5% in monkeys.

5. Excretion of the drug in rats and dogs was primarily via the bile. Approx. 1% of the dose was excreted in the urine of rats and dogs after oral dosing. In rats, at least 50% of an oral dose was excreted in bile as the glucuronide conjugate of parent drug.     

Disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine in mice, dogs, and monkeys

The metabolic disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-AraA) has been studied in mice, dogs, and monkeys after iv administration. Following injection of 2-F-AraA (30 mg/m2) into mice, serum levels fell with apparent half-lives of 17 min for the alpha-phase and 72 min for the beta-phase. For dogs given the same dose, these values were less than 5 and 112 min, and, for monkeys, 26 and 125 min, respectively. A higher concentration of metabolites was present in the serum of dogs than in the serum of mice and monkeys. Phosphorylated derivatives of 2-F-AraA were present in each of several mouse tissues examined; liver contained the highest concentration. In 24 hr, mice excreted more than half of the administered compound in the urine as unchanged 2-F-AraA. For dogs given a dose of 400 mg/m2, a single phase of disappearance of the drug (t1/2 = 130 min) was observed. For a single monkey, there were two phases, with half-lives of 15 min and 6.7 hr. In the urine, monkeys excreted about half of either dose as parent compound; but dogs excreted only about one-fourth as unchanged drug. These data indicate that 2-F-AraA is extensively metabolized by dogs but less so by mice and monkeys.     

Disposition and metabolism of the angiotensin-converting enzyme inhibitor [4S-[4 alpha, 7 alpha, (R*), 12b beta]]-7-[S-(1-ethoxycarbonyl-3- phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid in monkeys and dogs.

[4S-[4 alpha, 7 alpha, (R*),12b beta]]-7-[S- (1-ethoxycarbonyl-3-phenylpropyl)amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid (MDL 27,210) is the ethyl ester prodrug of a potent angiotensin-converting enzyme inhibitor, MDL 27,088. After a single dose of [14C]MDL 27,210 (3 mg/kg iv), MDL 27,210 was rapidly eliminated from the plasma of monkeys and dogs with a terminal half-life of approximately 0.3 hr. The steady-state volume of distribution was 0.15 liter/kg in dogs and 0.28 liter/kg in monkeys. Monkeys excreted 52% of the 14C dose in the feces and 41% in the urine; dogs excreted 80% of the 14C dose in the feces and 14% in the urine. The presence of a large fraction of the 14C dose in the feces of both species following iv administration suggests that significant biliary excretion occurred. MDL 27,210 administered iv to monkeys and dogs was rapidly and extensively (greater than 99.9%) metabolized, primarily to its diacid metabolite, MDL 27,088. The half-life of MDL 27,088 was 2.2 hr in dogs and 3.6 hr in monkeys.     

Comparison of 2,2'4,4',5,5'-Hexachloro[14C]biphenyl Levels in Different Adipose Tissues of Dogs and Monkeys

Comparison of 2,2',4,4',5,5'-Hexachloro[¹⁴C]biphenyl Levelsin Different Adipose Tissues of Dogs and Monkeys. RYERSON, B.A., CARTER, D. E., AND SIPES, 1. G. (1984). Fundam. Appl. Toxicol.4, 120–124. The polychlorinated biphenyl isomer, 2,2',4,4',5,5'-hexachloro[¹⁴C]biphenyl(2,4,5-HCB) was administered as a single iv dose at 0.6 mg/kgto dogs and monkeys. Adipose tissue, which included omentum,pericardial perirenal, peritesticular, and subcutaneous fat,and blood were collected at various termination times and analyzedfor total ¹⁴C and the parent hexachlorobiphenyl (HCB). Significantdifferences (p < 0.0005) in the total hexachlorobiphenylconcentration as measured by total radioactivity (¹⁴C equivalents)were noted in the various adipose tissues and in the same adiposetissues with time. Peritesticular fat was consistently lowerin the concentration of ¹⁴C equivalents than the other adiposetissues, which were nearly equal. The concentrations in subcutaneousfat samples were inconsistent. Total ¹⁴C equivalent concentrationsin the adipose tissues either peaked or reached a maximum atDay 1 and Day 4 for dog and monkey, respectively. However, parentHCB fat/blood ratios continually increased over the time courseof the experiment, because concentrations in blood decreasedmore rapidly than those in adipose tissue.     

Biliary excretion of cadmium in the rat,rabbit, and dog

The fecal elimination of cadmium is more important than urinary elimination. Within 1 week after iv administration of cadmium to the rat (1 mg/kg), 17% is excreted into the feces and less than 0.5% into the urine. However, of the amount excreted into the feces in 1 week, 85% is excreted within 2 days. The disappearance of ¹⁰⁹Cd from the plasma and its excretion into bile were measured for 2 hr after the iv administration of 0.1, 0.3, 1.0, and 3.0 mg/kg of cadmium to rats. The bile/plasma concentration ratio of cadmium was highly dose dependent; at the lowest dose, it was 2.6, and, at the highest dose, it was 133. The bile/plasma ratio was greater than 1 because the concentration of cadmium in the liver was 100 to 700 times higher than in the plasma. However, the bile concentration of cadmium was equal to or much lower than that in the liver; at the lowest dose (0.1 mg/kg), the concentration of cadmium in the bile was less than 1% of that in the liver. The relationship of the dose of cadmium to its biliary excretion was also reflected in the percentage of cadmium excreted into the bile within 2 hr, which ranged from 0.23 to 9% as the dose was increased from 0.1 to 3 mg/kg. The biliary excretion of cadmium was increased approximately four times as the temperature of the rat was increased from 30 to 40°C. The effect of 4 days of pretreatment with phenobarbital, spironolactone, pregnenolone-16α-carbonitrile, or 3-methylcholanthrene on the biliary excretion of cadmium was measured; only phenobarbital significantly increased its excretion. Marked species variation in the biliary excretion was observed. Rabbits excreted cadmium at a rate of about $\text{1}\text{6th}$, and dogs excreted cadmium at a rate of about $\text{1}\text{300th}$ of that observed in the rat. These results suggest that, while biliary excretion is the main route for cadmium elimination, the rate at which it is excreted appears to be highly dependent on the time after administration, the dose, and the species employed. This rate is not as responsive to alteration in the temperature of the animal or to administration of microsomal enzyme inducers as is that of some other metals.     

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.