Disposition and metabolism of cetrorelix, a potent luteinizing hormone-releasing hormone antagonist, in rats and dogs.

Disposition and metabolism of cetrorelix was studied in intact and bile duct-cannulated rats and dogs after s.c. injection. An s.c. dose of 0.1 mg/kg [(14)C]cetrorelix was rapidly and completely absorbed in rats. T(max) in plasma and most tissues was at 2 h. Radioactivity at the injection site in rats declined to 10% by 24 h. The extent of (14)C absorption in rats calculated from excretion until 264 h was 94%. Exposure of the target organ pituitary gland was demonstrated with a time course similar to plasma but on a higher level. Rats excreted 69.6% of radioactivity via feces and 24. 3% into urine. Excretion was nearly complete within 48 h. No enteral reabsorption was detected. In dogs t(max) in plasma was 1.3 h. (14)C- and cetrorelix-plasma levels were similar until 24 h, indicating a negligible amount of metabolites. A dose of 1 mg/kg in dogs showed an increasing influence of a slow absorption phase (flip-flop). In dogs equal amounts of the (14)C dose were found within 192 h in feces and urine, 46 and 48%, respectively. In urine of both species, only intact cetrorelix was detected. In bile and feces of both species qualitatively the same metabolites were found, characterized as truncated peptides of the parent decapeptide. The major metabolite occurring in bile of both species was the (1-7)heptapeptide. The amounts of the (1-4)tetrapeptide in feces of rats but not in that of dogs increase with time, suggesting additional degradation of the peptide in the gastrointestinal tract of rats by enteric metabolization.     

Oxymorphone hydrochloride, a potent opioid analgesic, is not carcinogenic in rats or mice.

Despite their long history of chronic use, little information is available regarding the carcinogenicity of opioid analgesics. Oxymorphone is a potent morphinan-type mu-opioid analgesic used for treatment of moderate-to-severe pain. Oxymorphone was tested for carcinogenicity in Crl:CD IGS BR rats and CD-1 mice. Oxymorphone hydrochloride was administered orally once daily for 2 years to rats at doses of 2.5, 5 and 10 mg/kg/day (males) and 5, 10 and 25 mg/kg/day (females), and mice at 10, 25, 75 and 150 mg/kg/day (65 animals per sex per group; 100 animals per sex in controls). In rats, survival was generally higher than controls in oxymorphone-treated groups, attributable to lower body weight gain. In mice, survival was generally higher than controls in females at all doses and males given < or = 25 mg/kg/day but lower in males given > or = 75 mg/kg/day due to a high incidence of obstructive uropathy. Opioid-related clinical signs and reduced body weight gain occurred in both species throughout the study. Nonneoplastic findings associated with oxymorphone pharmacology included ocular and pulmonary changes in rats considered secondary to inhibition of blinking and mydriasis, and antitussive activity, respectively, and urinary tract and renal findings in mice considered secondary to urinary retention. There was no target organ toxicity, and no increase in any neoplastic lesions attributed to oxymorphone. Plasma oxymorphone levels achieved in these studies exceeded those in patients taking high therapeutic doses of oxymorphone (Area under the curve [AUC(0-24 h)] values up to 5.6-fold and 64-fold in rats and mice, respectively). Oxymorphone is not considered to be carcinogenic in rats or mice under the conditions of these studies.     

Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey > rat approximately human > dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.     

Pharmacokinetics and tissue distribution of a new carbapenem,DA-1131, after intravenous administration to mice,rats, rabbits and dogs

The pharmacokinetic parameters including tissue distribution and/or biliary excretion of DA-1131, a new carbapenem, were evaluated after intravenous (iv) administration to mice, rats, rabbits, and dogs. After iv administration to mice (20, 50, 100, and 200 mg kg⁻¹), rats (50, 100, 200, and 500 mg kg⁻¹), rabbits (20, 50, 100, and 200 mg kg⁻¹), and dogs (10, 20, 50, 100, and 200 mg kg⁻¹), the pharmacokinetic parameters of DA-1131 seemed to be independent of DA-1131 doses studied in all four animal species. However, the renal clearance and percentage of iv dose of DA-1131 excreted in 24 h urine as unchanged drug decreased significantly in rabbits (from 200 mg kg⁻¹) and dogs (from 100 mg kg⁻¹) due to reduced kidney function induced by DA-1131. The creatinine clearance decreased significantly in rabbits at 200 mg kg⁻¹ compared with that in the control rabbits (0.466 versus 4.31 mL min⁻¹ kg⁻¹). Renal active secretion of DA-1131 was observed in rabbits and was less considerable in rats, but renal active reabsorption of DA-1131 was observed in dogs. Although DA-1131 was widely distributed in all tissues studied in mice (20–200 mg kg⁻¹), rats (200 mg kg⁻¹), rabbits (50 mg kg⁻¹), and dogs (50 mg kg⁻¹), affinity of DA-1131 for tissues was low: the tissue-to-plasma concentration ratios were greater than unity only in the kidney and/or liver. The low affinity of DA-1131 for tissues was also supported by relatively low values of the apparent volume of distribution at steady state in rats (147–187 mL kg⁻¹), rabbits (91.7–148 mL kg⁻¹), and dogs (243–298 mL kg⁻¹). The contribution of biliary excretion of unchanged DA-1131 to nonrenal clearance of DA-1131 seemed to be minor in rats (200 mg kg⁻¹) and dogs (50 mg kg⁻¹); the percentages of iv dose excreted in 8 h bile as unchanged DA-1131 were 1.76 and 2.71% after iv administration of the drug to rats and dogs, respectively. © 1998 John Wiley & Sons, Ltd.     

The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs.

Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [(14)C]rofecoxib precluded accurate determinations of half-life, AUC(0-infinity) (area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [(14)C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with C(max) occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [(14)C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-beta-D-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3',4'-dihydrodiol, and 4'-hydroxyrofecoxib sulfate were less abundant, whereas cis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-beta-D-glucuronide (urine), trans-3, 4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile).     

Disposition of 6-chloro-2-pyridylmethyl nitrate, a new anti-anginal compound, in rats and dogs

1. The absorption, distribution, metabolism and excretion of 6-chloro-2- pyridylmethyl nitrate, a new anti-anginal compound, were investigated in rats and dogs after intravenous and peroral administration of the 14C-labelled or unlabelled drug. 2. The half-lives of plasma levels for the alpha and beta phase and systemic availability were 6 min, 42 min and 26-50% respectively in rats, and 8 min, 66 min and 5% respectively in dogs. 3. Radioactivity was rapidly distributed in the tissues of rats, and recovered mainly in the 0-24 h urine (95% of dose within 24 h) with no excretion in the expired air. 4. Several metabolites were detected on t.l.c. of rat and dog urine, and four were identified as N-(chloro-2-pyridylcarbonyl)-glycine (M1, 56%), N-acetyl-S-(6- chloro-2-pyridylmethyl)-L-cysteine (M2, 29%), 6-chloro-2-pyridinecarboxylic acid (M3, 5%) and 6-chloro-2-pyridylmethyl. beta-D-glucuronate (M4, 7%). No unchanged drug was excreted.     

Disposition of 6-chloro-2-pyridylmethyl nitrate,a new anti-anginal compound,in rats and dogs

1. The absorption, distribution, metabolism and excretion of 6-chloro-2-pyridylmethyl nitrate, a new anti-anginal compound, were investigated in rats and dogs after intravenous and peroral administration of the ¹⁴C-labelled or unlabelled drug.

2. The half-lives of plasma levels for the α and β phase and systemic availability were 6 min, 42 min and 26–50% respectively in rats, and 8 min, 66 min and 5% respectively in dogs.

3. Radioactivity was rapidly distributed in the tissues of rats, and recovered mainly in the 0–24 h urine (95% of dose within 24 h) with no excretion in the expired air.

4. Several metabolites were detected on t.l.c. of rat and dog urine, and four were identified as N-(chloro-2-pyridylcarbonyl)-glycine (M1, 56%), N-acetyl-S-(6-chloro-2-pyridylmethyl)-L-cysteine (M2, 29%), 6-chloro-2-pyridinecarboxylic acid (M3, 5%) and 6-chloro-2-pyridylmethyl. β-D-glucuronate (M4, 7%). No unchanged drug was excreted.     

Respiratory and cardiovascular toxicity studies of a novel antiprion compound, GN8, in rats and dogs

Prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders for which no effective curative or prophylactic method has been established. Recently, we discovered a novel antiprion compound, GN8. Administration of GN8 was found to prolong the survival of prion-infected mice. The aim of this study was to characterize the toxicological and pharmacological features of GN8 in rats and dogs treated via a single intravenous injection. Minimum lethal doses of GN8 were estimated to be approximately 60 and 40 mg/kg in rats and dogs, respectively. In the respiratory toxicity experiments, GN8 was administered to rats at doses of 0, 15.6, and 46.9 mg/kg, and rats were observed for consciousness, behavior, autonomic nervous symptoms, and body weights. GN8 was found to have little adverse effect on the rat respiratory system at a dose of 46.9 mg/kg. In the cardiovascular toxicity experiments, GN8 was administered to dogs at doses of 0, 7.8, and 31.3 mg/kg, and dogs were observed similarly. Although GN8 was found to have a slight effect on the cardiovascular system at a dose of 31.3 mg/kg, we did not find severe adverse effects of GN8 at doses sufficient for antiprion activity. This study would serve as a stepping stone to a clinical application of GN8 as an antiprion agent.     

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

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

Respiratory and cardiovascular toxicity studies of a novel antiprion compound,GN8, in rats and dogs

Prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders for which no effective curative or prophylactic method has been established. Recently, we discovered a novel antiprion compound, GN8. Administration of GN8 was found to prolong the survival of prion-infected mice. The aim of this study was to characterize the toxicological and pharmacological features of GN8 in rats and dogs treated via a single intravenous injection. Minimum lethal doses of GN8 were estimated to be approximately 60 and 40?mg/kg in rats and dogs, respectively. In the respiratory toxicity experiments, GN8 was administered to rats at doses of 0, 15.6, and 46.9?mg/kg, and rats were observed for consciousness, behavior, autonomic nervous symptoms, and body weights. GN8 was found to have little adverse effect on the rat respiratory system at a dose of 46.9?mg/kg. In the cardiovascular toxicity experiments, GN8 was administered to dogs at doses of 0, 7.8, and 31.3?mg/kg, and dogs were observed similarly. Although GN8 was found to have a slight effect on the cardiovascular system at a dose of 31.3?mg/kg, we did not find severe adverse effects of GN8 at doses sufficient for antiprion activity. This study would serve as a stepping stone to a clinical application of GN8 as an antiprion agent.     

Disposition of RS-26306, a potent luteinizing hormone-releasing hormone antagonist, in monkeys and rats after single intravenous and subcutaneous administration.

The metabolic disposition of RS-26306, a new potent luteinizing hormone-releasing hormone antagonist, was studied in rats and monkeys after single i.v. and sc administration with the 3H-labeled compound. Plasma pharmacokinetics after iv administration were: CLs = 2.5 ml/min/kg, Vd beta = 0.29 liter/kg, t1/2 = 1.4 hr (rats), and CLs = 0.8 ml/min/kg, Vd beta = 0.32 liter/kg, t1/2 = 5.1 hr (monkeys). Cmax and Tmax in rats were 0.53 micrograms/ml and 4 hr after the 1 mg/kg sc dose, and were 1.07 micrograms/ml and 12 hr after the 10 mg/kg sc dose. AUC0-infinity after the 10 mg/kg sc dose in rats was seven times that after the 1 mg/kg sc dose. Apparent plasma disappearance t1/2 in rats were 3.6 and 15.2 hr, respectively, after the 1 and 10 mg/kg sc doses. An average of 12 and 4% of dose radioactivity remained at the injection site in rats 3 and 10 days, respectively, after a 10 mg/kg sc dose. In monkeys, Tmax after a 1 mg/kg sc dose was 0.5 hr for three animals but was 24 hr for the fourth animal, although plasma of this monkey contained substantial levels of RS-26306 between 15 min and 24 hr. Apparent plasma t1/2 in monkeys after a 1 mg/kg sc dose was at least 19 hr. Our data suggest depot formation after sc doses. In vitro plasma binding amounted to 82-84%. Excretion was mainly biliary: 12-25 and 55-84% of dose radioactivity was recovered in urine and feces, respectively, in both species. The biological samples contained only traces of 3H2O. Three metabolites, which were truncated peptides of the parent decapeptide, were identified in the rat bile. One of these was also present in the monkey plasma. The restricted enzymatic degradation of RS-26306, extensive plasma binding, and long circulating t1/2 of RS-26306 contribute to its prolonged activity in animal models and in humans.     

Sex difference in the excretion of zenarestat in mice, rats, dogs and humans.

1. Mice show a sex difference in the excretion of zenarestat similar to that seen in rats, but dogs and humans show no significant sex difference. 2. Female rats and mice, and both sexes of dogs and humans, appear to possess an active secretory mechanism in the renal excretion of zenarestat, which is lacking or relatively inactive in male rats and mice.     

Suprofen, a potent antagonist of sodium urate crystal-induced arthritis in dogs.

A standardized sodium urate-induced arthritis test in dogs is described in detail. A microcrystalline suspension of 20 mg/ml in 0.9% NaCl was injected into one of the stifle joints in a volume of 0.5 ml and motor impairment of the dogs was scored every 30 min over a period of 8 h. A direct quantitative comparison was made of the anti-arthritic activity of acetyl-salicylic acid, phenylbutazone, indometacin and alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen). All compounds were given by oral gavage immediately after the sodium urate injection. Among the compounds studied suprofen was the most potent antagonist of sodium urate-induced arthritis in dogs. Comparing the ED50 values suprofen was about 4 times as potent as indometacin, 9 times as potent as phenylbutazone and 60 times as potent as acetyl-salicylic acid.     

Toxicology of vindesine (desacetyl vinblastine amide) in mice, rats, and dogs.

Comparative acute intravenous toxicity studies of vinblastine sulfate (VLB), vincristine sulfate (VCR), and vindesine in mice and rats indicated that vindesine was more toxic than VLB and less toxic than VCR. Rats were able to tolerate larger repeated doses of vindesine than dogs. Rats given intravenous doses totaling 0.15 mg/kg-wk vindesine for 3 months developed no remarkable signs of toxicity. Doses of 0.3 mg/kg-wk or greater produced anorexia, depressed blood cell counts, atrophic intestinal mucosa, inhibition of spermatogenesis, extramedullary hematopoiesis, and infections. Dogs were given total weekly intravenous doses of 0.04, 0.08, 0.1, or 0.16 mg/kg vindesine for 3 months. The only observed effect in the two lower dose groups was inhibition of spermatogenesis. Groups receiving 0.1 or 0.16 mg/kg developed leukopenia, slight erythropenia, inhibition of spermatogenesis, focal skeletal muscle degeneration, elevated lactic dehydrogenase, and an increase in bone marrow myeloid: erythroid ratio. No evidence of functional or structural changes in neural tissues was found. The above effects are common to animals given VCR at lower doses and for a shorter test period. It is therefore concluded that vindesine is less toxic in animals than VCR.     

The pharmacokinetics of indecainide in mice, rats, dogs, and monkeys

The pharmacokinetics of indecainide, a new antiarrhythmic agent, were studied in mice, rats, dogs, and monkeys. The drug was well absorbed in all species tested resulting in peak plasma levels of drug within 2 hr. The plasma half-life of indecainide after acute oral administration was 3-5 hr in rats, dogs, and monkeys but considerably shorter in mice. The plasma half-life of indecainide was dose-dependent in dogs and increased slightly with chronic dosing. Peak plasma levels of drug were also dose-dependent in dogs and monkeys. Fecal elimination was the primary route of excretion of the drug in rats and mice after oral dosing. Fifty per cent of the dose was excreted in the bile of rats which was then subject to enterohepatic circulation. Urinary elimination was the predominant excretory route in the dog. Tissue distribution of radioactivity in rats showed that tissues which first encounter the drug have the highest levels of radioactivity. The highest concentrations were found in the stomach, intestine, liver, and kidney, whereas very low levels were observed in the fat and brain. Except for liver and kidney, only very low levels were present after 24 hr.     

Tulobuterol: one-month intravenous safety studies in rats and dogs

Tulobuterol was given intravenously to rats and dogs at dosages of 1, 5, or 25 mg/kg/day and 0.6, 2, or 6 mg/kg/day, respectively. The no-toxic-effect dosages were 5 mg/kg/day in rats and 6 mg/kg/day in dogs. Two rats died at 25 mg/kg/day. Convulsions, jerking movements, hyperactivity, tremors, hypoactivity and ptyalism were observed in rats given 25 mg/kg/day. Restlessness, ptyalism and hypoactivity were also observed in dogs at 2 and 6 mg/kg/day. Cutaneous and/or mucosal erythema were observed in rats and dogs at all dosages. Increased body weight gain occurred in drug-treated rats and in mid- and high-dose female dogs. Slight elevations in serum creatinine and BUN were seen in rats and dogs at the highest dosages. Heart weights were increased in rats at all dosages after 1 month of treatment and in rats given 25 mg/kg/day after 2 weeks of recovery. There were no treatment-related morphologic changes in either species.     

Disposition and metabolic fate of prasugrel in mice,rats, and dogs

The disposition and metabolism of prasugrel, a thienopyridine prodrug and a potent inhibitor of platelet aggregation in vivo, were investigated in mice, rats, and dogs. Prasugrel was rapidly absorbed and extensively metabolized. In the mouse and dog, maximum plasma concentration of radioactivity was observed in less than 1?h after an oral [¹⁴C]prasugrel dose. Most of the administered prasugrel dose was recovered in the faeces of rats and dogs (72% and 52–73%, respectively), and in mice urine (54%). Prasugrel is hydrolysed by esterases to a thiolactone, which is subsequently metabolized to thiol-containing metabolites. The main circulating thiol-containing metabolite in the three animal species is the pharmacologically active metabolite, R-138727. The thiol-containing metabolites are further metabolized by S-methylation and conjugation with cysteine.     

Disposition and metabolic fate of prasugrel in mice, rats, and dogs

The disposition and metabolism of prasugrel, a thienopyridine prodrug and a potent inhibitor of platelet aggregation in vivo, were investigated in mice, rats, and dogs. Prasugrel was rapidly absorbed and extensively metabolized. In the mouse and dog, maximum plasma concentration of radioactivity was observed in less than 1 h after an oral [14C]prasugrel dose. Most of the administered prasugrel dose was recovered in the faeces of rats and dogs (72% and 52-73%, respectively), and in mice urine (54%). Prasugrel is hydrolysed by esterases to a thiolactone, which is subsequently metabolized to thiol-containing metabolites. The main circulating thiol-containing metabolite in the three animal species is the pharmacologically active metabolite, R-138727. The thiol-containing metabolites are further metabolized by S-methylation and conjugation with cysteine.