Comparative evaluation of absorption, distribution, and excretion of YM758, a novel If channel inhibitor, between albino and non-albino rats

1. YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. The absorption, distribution, and excretion of YM758 have been investigated in albino and non-albino rats after a single oral administration of (14)C-YM758 monophosphate. 2. YM758 was well absorbed from all segments of the gastrointestinal tract except for the stomach. After oral administration, the ratio of AUC(0-1 h) between the plasma concentrations of radioactivity and the unchanged drug was estimated to be 17.7%, which suggests metabolism. 3. The distribution of the radioactivity derived from (14)C-YM758 in tissues was evaluated both in albino and non-albino rats. The radioactivity concentrations in most tissues were higher than those in plasma, which indicates that the radioactivity is well distributed to tissues. Extensive accumulation and slower elimination of radioactivity were noted in the thoracic aorta of albino and non-albino rats as well as in the eyeballs of non-albino rats. The recovery rates of radioactivity in urine and bile after oral dosing to bile duct-cannulated albino rats were 17.8% and 57.3%, respectively. 4. These results suggest that YM758 was extensively absorbed, subjected to metabolism, and excreted mainly into the bile after oral administration to rats, and extensive accumulation of the unchanged drug and/or metabolites into tissues such as the thoracic aorta and eyeballs was observed.     

Comparative evaluation of absorption,distribution, and excretion of YM758, a novel If channel inhibitor,between albino and non-albino rats

1. YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. The absorption, distribution, and excretion of YM758 have been investigated in albino and non-albino rats after a single oral administration of ¹⁴C-YM758 monophosphate.

2. YM758 was well absorbed from all segments of the gastrointestinal tract except for the stomach. After oral administration, the ratio of AUC_{0–1 h} between the plasma concentrations of radioactivity and the unchanged drug was estimated to be 17.7%, which suggests metabolism.

3. The distribution of the radioactivity derived from ¹⁴C-YM758 in tissues was evaluated both in albino and non-albino rats. The radioactivity concentrations in most tissues were higher than those in plasma, which indicates that the radioactivity is well distributed to tissues. Extensive accumulation and slower elimination of radioactivity were noted in the thoracic aorta of albino and non-albino rats as well as in the eyeballs of non-albino rats. The recovery rates of radioactivity in urine and bile after oral dosing to bile duct-cannulated albino rats were 17.8% and 57.3%, respectively.

4. These results suggest that YM758 was extensively absorbed, subjected to metabolism, and excreted mainly into the bile after oral administration to rats, and extensive accumulation of the unchanged drug and/or metabolites into tissues such as the thoracic aorta and eyeballs was observed.     

Absorption,distribution, metabolism and excretion of telmesteine,a mucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of (14)C-telmesteine in the Sprague-Dawley rat. 2. (14)C-telmesteine was rapidly absorbed after oral dosing (20 and 50 mg kg(-1)) with an oral bioavailability of >90% both in male and female rats. The C(max) and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats. 3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30 min after dosing was relatively low with a range of 0.1-0.8 except for excretory organs. 4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma. 5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Absorption,distribution, metabolism and excretion of telmesteine,amucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of ¹⁴C-telmesteine in the Sprague–Dawley rat.

2. ¹⁴C-telmesteine was rapidly absorbed after oral dosing (20 and 50mg kg^-1) with an oral bioavailability of > 90% both in male and female rats. The C_max and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats.

3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30min after dosing was relatively low with a range of 0.1–0.8 except for excretory organs.

4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma.

5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Disposition and metabolism of (2S,3S,4R)-N'-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N'-benzylguanidine, a novel neuroprotective agent for ischemia-reperfusion damage, in rats

The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [(14)C]-KR31378 to rats. [(14)C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24 h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24 h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.     

Pharmacokinetics, tissue distribution, and excretion of sitafloxacin, a new fluoroquinolone antibiotic, in rats, dogs, and monkeys

The pharmacokinetics, tissue distribution and excretion of sitafloxacin (CAS 127254-12-0, DU-6859a) were investigated in rats, dogs, and monkeys following single intravenous or single oral administration of 14C-labelled sitafloxacin at a dose of 4.69 mg/kg. Following single administration of the oral dose, serum concentrations of radioactivity peaked at 0.5 h in rats, 2.3 h in dogs, and 2.5 h in monkeys. The apparent absorption ratios of 14C-sitafloxacin based on the AUC0-infinity were 31%, 51%, and 93% in rats, dogs, and monkeys, respectively. In rats, the drug-related radioactivity had been distributed to most organs and tissues 30 min after oral dosing, and had been essentially eliminated after 24 h. The highest levels of radioactivity were observed in the kidneys and liver, whereas the concentrations in the cerebrum and spinal cord were much lower than the serum value. The urinary recoveries of radioactivity after intravenous dosing were 45.5 % in rats, 32.3 % in dogs, and 77.8 % in monkeys. In bile duct-cannulated rats, 57.8 % of the orally administered radioactivity was excreted in the bile within 48 h, and at least 45 % of the sitafloxacin-related material secreted in the bile was re-absorbed from the gastrointestinal tract. These results indicate that sitafloxacin is rapidly absorbed and widely distributed into various tissues. Sitafloxacin-related material is eliminated primarily through both renal and biliary excretion in rats, and possibly in dogs, whereas renal excretion is the major route of elimination in monkeys.     

Absorption, distribution and excretion of the new thienopyridine agent prasugrel in rats

Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, (14)C-prasugrel or prasugrel was administered to rats at a dose of 5 mg kg(-1). After oral and intravenous dosing, the values of AUC(0-infinity) of total radioactivity were 36.2 and 47.1 microg eqx h ml(-1), respectively. Oral dosing of unlabeled prasugrel showed the second highest AUC(0-8) of the active metabolite of six metabolites analyzed. Quantitative whole body autoradiography showed high radioactivity concentrations in tissues for absorption and excretion at 1 h after oral administration, and were low at 72 h. The excretion of radioactivity in the urine and feces were 20.2% and 78.7%, respectively, after oral dosing. Most radioactivity after oral dosing was excreted in bile (90.1%), which was reabsorbed moderately (62.4%). The results showed that orally administered prasugrel was rapidly and fully absorbed and efficiently converted to the active metabolite with no marked distribution in a particular tissue.     

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine,a novel neuroprotective agent for ischemia-reperfusion damage,in rats

The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [¹⁴C]-KR31378 to rats. [¹⁴C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24?h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24?h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat.

Donepezil hydrochloride (Aricept) is a drug for the treatment of Alzheimer's disease. The absorption, distribution, metabolism, and excretion of donepezil were investigated in male Sprague-Dawley rats after a single oral administration. Orally administered (14)C-labeled donepezil was absorbed rapidly. The plasma level of unchanged donepezil declined more rapidly than that of radioactivity, and the brain level of radioactivity declined almost in parallel with the plasma level of unchanged donepezil. The ratio of donepezil to total radioactivity in brain was 86.9 to 93.0%, indicating low permeability of the metabolites through the blood-brain barrier. No heterogeneous localization of radioactivity was recognized in the brain and the concentration in each part of the brain was 1.74 to 2.24 times the plasma concentration. Cumulative biliary, urinary, and fecal excretion of radioactivity in bile duct-cannulated rats was 72.9, 24.4, and 8.84%, respectively, of the administered radioactivity at 48 h after administration. These results indicate that the absorption of donepezil is almost complete, and that its metabolites are mainly excreted into feces through the bile and some of them are subject to enterohepatic circulation. The metabolism of donepezil was extensive in rats and involved O-demethylation, aromatic hydroxylation, N-dealkylation, N-oxidation, and glucuronide conjugation of O-demethylate. The structures of the metabolites were determined by mass spectrometry and (1)H-NMR analysis. In plasma, urine, and bile, O-glucuronides accounted for the majority of the radioactivity, and in brain, unchanged donepezil was mostly detected. No metabolites were found in brain. There was no notable accumulation of radioactivity in whole blood and tissues.     

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Absorption,distribution and excretion of lacidipine,a dihydropyridine calcium antagonist,in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog).

2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism.

3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug.

4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species.

5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses.

6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration.

7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog

We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog.

2. Unavailability of YM17E was 5–9% at oral doses of 3–30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30mg/kg in dog.

3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with (hat of unchanged drug.

4. When ¹⁴C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation.

5. After oral administration of ¹⁴C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration.

6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA: cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites.

7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism.

8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of ¹⁴C-YM17E.     

Hepatobiliary transport of YM466, a novel factor Xa inhibitor, in rats.

YM466, a novel factor Xa inhibitor, is a hydrophilic compound with a carboxylic acid moiety. Previous studies in rats have shown that YM466 does nor undergo metabolism but is excreted into the bile and urine in unchanged form. Thus, in this study, we investigated in vivo hepatobiliary transport, focusing in particular on multidrug resistance-associated protein 2 (Mrp2/Abcc2)-mediated transport. The hepatobiliary transport of YM466 was investigated after its systemic infusion into Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs), which lack Mrp2. When the binding of YM466 in the plasma and liver was examined, the bile-to-plasma concentration ratio and the liver-to-plasma concentration ratio for the unbound concentration in SDRs amounted to 32.2 and 2.83, respectively, suggesting concentrated transport. The bile-to-liver concentration ratio for the unbound concentration in EHBRs was not lower than that found for SDRs. These findings suggest that YM466 is excreted from the plasma into the bile in a concentrated manner; however, Mrp2 does not play a major role in biliary excretion.     

Pharmacokinetics, distribution and excretion of YM155 monobromide, a novel small-molecule survivin suppressant, in male and pregnant or lactating female rats

YM155 monobromide is a novel small-molecule survivin suppressant. The pharmacokinetics, distribution and excretion of YM155/[14C]YM155 were investigated using males and pregnant or lactating female rats after a single intravenous bolus administration. For the 0.1, 0.3 and 1 mg/kg YM155 doses given to male rats, increases in area under the plasma concentration-time curves were approximately proportional to the increase in the dose level. After administering [14C]YM155, radioactivity concentrations in the kidney and liver were highest among the tissues in both male and pregnant rats: e.g. 14.8- and 5.24-fold, respectively, and higher than in plasma at 0.1 h after dosing to male rats. The YM155 concentrations in the brain were lowest: 25-fold lower than in plasma. The transfer of radioactivity into fetuses was low (about 2-fold lower than in plasma). In lactating rats, the radioactivity was transferred into milk at a level 8- to 21-fold higher than for plasma. Radioactivity was primarily excreted in feces (64.0%) and urine (35.2%). The fecal excretion was considered to have occurred mainly by biliary excretion and partly by secretion across the gastrointestinal membrane from the blood to the lumen.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).     

The metabolic disposition of aprepitant, a substance P receptor antagonist, in rats and dogs.

The absorption, metabolism, and excretion of [14C]aprepitant, a potent and selective human substance P receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting, was evaluated in rats and dogs. Aprepitant was metabolized extensively and no parent drug was detected in the urine of either species. The elimination of drug-related radioactivity, after i.v. or p.o. administration of [14C]aprepitant, was mainly via biliary excretion in rats and by way of both biliary and urinary excretion in dogs. Aprepitant was the major component in the plasma at the early time points (up to 8 h), and plasma metabolite profiles of aprepitant were qualitatively similar in rats and dogs. Several oxidative metabolites of aprepitant, derived from N-dealkylation, oxidation, and opening of the morpholine ring, were detected in the plasma. Glucuronidation represented an important pathway in the metabolism and excretion of aprepitant in rats and dogs. An acid-labile glucuronide of [14C]aprepitant accounted for approximately 18% of the oral dose in rat bile. The instability of this glucuronide, coupled with its presence in bile but absence in feces, suggested the potential for enterohepatic circulation of aprepitant via this conjugate. In dogs, the glucuronide of [14C]aprepitant, together with four glucuronides derived from phase I metabolites, were present as major metabolites in the bile, accounting collectively for approximately 14% of the radioactive dose over a 4- to 24-h period after i.v. dosing. Two very polar carboxylic acids, namely, 4-fluoro-alpha-hydroxybenzeneacetic acid and 4-fluoro-alpha-oxobenzeneacetic acid, were the predominant drug-related entities in rat and dog urine.     

The disposition of radioactivity after administration of the anthelminthic methyl-14C-5-cyclopropylcarbonyl-2-benzimidazole carbamate (ciclobendazole) to rats and dogs

1. The disposition of radioactivity has been studied in rats and dogs after administration of a new anthelminthic agent, 14C-labelled methyl-5-cyclopropylcarbonyl-2-benzimidazole carbamate (14C-ciclobendazole). 2. An oral dose of 14C-ciclobendazole (4 mg/kg) to rats was rapidly absorbed and about 70% and 20% of the dose was excreted in the faeces and urine, respectively, during 2 days. Bile duct cannulated rats excreted about 80% of the dose in 48-h bile, about 2% in the faeces and about 10% in the urine showing that an oral dose was well-absorbed and that some enterohepatic circulation probably occurred. The excretion of radioactivity in the bile was less after i.v. administration. 3. An oral dose of 14C-ciclobendazole (4 mg/kg) to dogs was mainly eliminated during 2 days with about 80% of the dose in the faeces and only about 10% in the urine. Anaesthetised bile duct-cannulated dogs, excreted between 26% and 35% of an oral dose in the bile during 24 h and up to 58% of an oral dose was absorbed at this time. 4. The tissue distribution of radioactivity in rats and dogs after single or multiple oral doses of 14C-ciclobendazole (4 mg/kg) showed that there was no unusual accumulation or localisation of radioactivity in the measured tissues. Highest concentrations were present in the intestinal tract, liver and kidneys, organs associated with biotransformation and excretion and also in the lungs and adrenals. 5. After oral administration of 14C-ciclobendazole to rate at three different dose levels (4, 40 and 400 mg/kg), peak plasma levels occurred at 15-30 min and declined with similar half-lives (about 20 h). A comparison of peak concentrations and areas under the plasma concentration-time relationships showed that the absorption of ciclobendazole was probably dose-dependent, a lower proportion probably being absorbed at higher doses. After repeated daily oral dosing with 14C-ciclobendazole (4 mg/kg), there were no significant changes in either the daily plasma concentrations or the biological half-life measured after the last dose, indicating that ciclobendazole probably did not induce or inhibit its own metabolism when dosed repeatedly at 4 mg/kg. 6. A comparison of the areas under the plasma concentration-time relationships after oral, i.p. and i.v. administration of 14C-ciclobendazole to rates indicated that there was no signigicant uptake by the liver during first pass and that an oral dose was well absorbed by rats. 7. The peak plasma concentration in the dog, after an oral dose of 14C-ciclobendazole (4 mg/kg) was reached at about 30 min and declined with a half-life of about 3 h. 8. Ciclobendazole was probably well-absorbed by rats and dogs and excreted more rapidly by the latter species than by the former Relatively higher plasma concentrations of drug and/or metabolites were thus achieved in rats than in dogs.     

Pharmacokinetics of YM466, a new factor Xa inhibitor, in rats and dogs.

The pharmacokinetics of YM466, a selective inhibitor for factor Xa, was investigated after single intravenous and oral dosing to rats and dogs. After i.v. dosing, plasma YM466 concentration declined in a bi-phasic manner with a terminal elimination half-life of 1.4 h in rats and 0.8 h in dogs. Total plasma clearance values were 884 and 1212 ml/h/kg in rats and dogs, respectively. After oral dosing, plasma YM466 concentrations reached maximum within 2 h and increased in a dose-proportional manner in rats while increase was nonlinear in dogs. The absolute bioavailability of YM466 was 2.7-4.5% in rats, almost constant regardless of the dose levels investigated, while it was 6.9-24.6% in dogs, indicating nonlinear pharmacokinetics. The plasma protein binding of YM466 was 54.7-56.5% in rats and 45.2-49.0% in dogs and almost constant regardless of the concentration. No metabolism of YM466 was observed in an in vitro liver microsome study. These findings suggest that the low bioavailability of YM466 is attributable to the poor absorption not to the extensive metabolism.