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.     

Tissue distribution of YM758, a novel If channel inhibitor,in pregnant and lactating rats

In this study the tissue distribution of radioactivity in pregnant and lactating rats was investigated by quantitatively determining radioactivity concentrations and by whole-body autoradioluminograms after a single oral administration of ¹⁴C-YM758. In addition, the transfer of radioactivity into the reproductive tissues, foetus, and milk is discussed in terms of the localization of transporters in syncytiotrophoblast and mammary gland. The radioactivity concentrations in the liver were the highest of all the tissues and organs tested at all the sampling times. The radioactivity in main tissues (liver and kidney), including reproductive tissues (amniotic fluid, placenta, ovary, and uterus), was not retained for a long time, as in the plasma. The tissue/plasma (T/P) ratio of radioactivity in the foetus was below 1.0, which might be due to Mdr1-mediated export of YM758 into blood via the blood–placenta barrier since YM758 is a substrate for hMDR1, not for hBCRP/rBcrp. The T/P ratio of radioactivity in the maternal milk 1 and 4 h after oral administration of ¹⁴C-YM758 was 7.2 and 11.0, respectively. To understand better the distribution of new drugs into the reproductive tissues/milk, and to interpret further the results of reproductive safety studies for drug development, the contribution of transporters expressed in the blood–placenta barrier and mammary gland to the drug-transfer into placenta and milk should be considered.     

Absorption, distribution, metabolism and excretion of YM466, a novel factor Xa inhibitor, in rats

YM466 is a novel factor Xa inhibitor for the treatment of thrombosis. The absorption, distribution, metabolism and excretion of YM466 were investigated in male Fisher rats after a single oral administration. YM466 was absorbed rapidly from all segments of the gastrointestinal tract except the stomach. After oral dosing, the plasma concentration of (14)C-YM466 reached a maximum within 0.5 h, and declined rapidly with an elimination half-life of 0.64 h. The unchanged YM466 accounted for almost all of its radioactivity, suggesting a minimal metabolism in rats. This was also supported by the finding that no metabolites were observed in bile and urine after oral dosing of (14)C-YM466. The distribution of (14)C-YM466 in tissue was evaluated and the liver and kidney were the organs with radioactivity concentrations consistently higher than that of plasma. Cumulative biliary and urinary excretion of radioactivity in bile duct-cannulated rats was 29.5% and 7.6%, respectively, indicating prominent excretion into bile after oral dosing. This was consistent with the finding that 76.1% and 25.2% of radioactivity dosed were excreted to faeces and urine, respectively, after i.v. dosing. These results suggest that YM466 was rapidly absorbed and then subjected to biliary excretion with a minimal metabolism after oral dosing to rats.     

Tissue distribution of YM758, a novel If channel inhibitor, in pregnant and lactating rats

In this study the tissue distribution of radioactivity in pregnant and lactating rats was investigated by quantitatively determining radioactivity concentrations and by whole-body autoradioluminograms after a single oral administration of 14C-YM758. In addition, the transfer of radioactivity into the reproductive tissues, foetus, and milk is discussed in terms of the localization of transporters in syncytiotrophoblast and mammary gland. The radioactivity concentrations in the liver were the highest of all the tissues and organs tested at all the sampling times. The radioactivity in main tissues (liver and kidney), including reproductive tissues (amniotic fluid, placenta, ovary, and uterus), was not retained for a long time, as in the plasma. The tissue/plasma (T/P) ratio of radioactivity in the foetus was below 1.0, which might be due to Mdr1-mediated export of YM758 into blood via the blood-placenta barrier since YM758 is a substrate for hMDR1, not for hBCRP/rBcrp. The T/P ratio of radioactivity in the maternal milk 1 and 4 h after oral administration of 14C-YM758 was 7.2 and 11.0, respectively. To understand better the distribution of new drugs into the reproductive tissues/milk, and to interpret further the results of reproductive safety studies for drug development, the contribution of transporters expressed in the blood-placenta barrier and mammary gland to the drug-transfer into placenta and milk should be considered.     

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.     

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).     

Disposition and metabolism of TAK-438 (vonoprazan fumarate), a novel potassium-competitive acid blocker,in rats and dogs

1.?Following oral administration of [¹⁴C]TAK-438, the radioactivity was rapidly absorbed in rats and dogs. The apparent absorption of the radioactivity was high in both species.

2.?After oral administration of [¹⁴C]TAK-438 to rats, the radioactivity in most tissues reached the maximum at 1-hour post-dose. By 168-hour post-dose, the concentrations of the radioactivity were at very low levels in nearly all the tissues. In addition, TAK-438F was the major component in the stomach, whereas TAK-438F was the minor component in the plasma and other tissues. High accumulation of TAK-438F in the stomach was observed after oral and intravenous administration.

3.?TAK-438F was a minor component in the plasma and excreta in both species. Its oxidative metabolite (M-I) and the glucuronide of a secondary metabolite formed by non-oxidative metabolism of M-I (M-II-G) were the major components in the rat and dog plasma, respectively. The glucuronide of M-I (M-I-G) and M-II-G were the major components in the rat bile and dog urine, respectively, and most components in feces were other unidentified metabolites.

4.?The administered radioactive dose was almost completely recovered. The major route of excretion of the drug-derived radioactivity was via the feces in rats and urine in dogs.     

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.     

Pharmacokinetics and metabolite profiling of fimasartan,a novel antihypertensive agent,in rats

Abstract

1.?The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats.

2.?Unlabeled fimasartan or radiolabeled [¹⁴C]fimasartan was dosed by intravenous injection or oral administration to rats. Concentrations of unlabeled fimasartan in the biological samples were determined by a validated LC/MS/MS assay. Total radioactivity was quantified by liquid scintillation counting and the radioactivity associated with the metabolites was analyzed by using the radiochemical detector. Metabolite identification was conducted by product ion scanning using LC/MS/MS.

3.?After oral administration of [¹⁴C]fimasartan, total radioactivity was found primarily in feces. In bile duct cannulated rats, 58.8?±?14.4% of the radioactive dose was excreted via bile after oral dosing. Major metabolites of fimasartan including the active metabolite, desulfo-fimasartan, were identified, yet none represented more than 7.2% of the exposure of the parent drug. Fimasartan was rapidly and extensively absorbed and had an oral bioavailability of 32.7–49.6% in rats. Fimasartan plasma concentrations showed a multi-exponential decline after oral administration. Double peaks and extended terminal half-life were observed, which was likely caused by enterohepatic recirculation.

4.?These results provide better understanding on the pharmacokinetics of fimasartan and may aid further development of fimasartan analogs.     

Absorption,distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats

The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of ¹⁴C‐ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart and plasma. Liquid chromatography‐nuclear magnetic resonance spectroscopy data revealed that O‐glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. No indication was found that the acyl glucuronide reacted with proteins in plasma or tissues. When ¹⁴C‐ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of the administered radioactivity, respectively. After a single oral administration of ¹⁴C‐ASP3258 to bile‐cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of the administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258‐derived radioactivity. In vitro metabolic profiles were relatively similar among the species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy and safety profiles in humans and other species. Copyright © 2014 John Wiley & Sons, Ltd.     

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.     

Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats,dogs and monkeys

1.?This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs.

2.?After oral administration of [¹⁴C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90% of the dose, mainly in the faeces. Biliary excretion was the major elimination pathway for [¹⁴C]MRE-269 as well as [¹⁴C]selexipag, while renal elimination was of little importance. [¹⁴C]Selexipag-related radioactivity was secreted into the milk in lactating rats.

3.?Plasma was analysed for total radioactivity, selexipag and MRE-269 in rats and monkeys. Selexipag was negligible in rat plasma due to extensive metabolism, and MRE-269 was present in rat and monkey plasma. A species difference was clearly evident when selexipag was incubated in rat, dog and monkey plasma.

4.?Total radioactivity was rapidly distributed to tissues. The highest concentrations were found in the bile duct and liver without significant accumulation or persistence, while there was limited melanin-associated binding, penetration of the blood–brain barrier and placental transfer of drug-related materials.     

Metabolic disposition of gefitinib,an epidermal growth factor receptor tyrosine kinase inhibitor,in rat,dog and man

1.?Following oral administration of [¹⁴C]-gefitinib to albino and pigmented rats, radioactivity was widely and rapidly distributed, with the highest levels being found in liver, kidney, lung and gastrointestinal tract, but with only low levels penetrating the brain. Levels of radioactivity persisted in melanin-containing tissues (pigmented eye and skin).

2.?Binding to plasma proteins was high (86–94%) across the range of species examined and was 91% in human plasma. Substantial binding occurred to both human serum albumin and α-1 acid glycoprotein.

3.?Following oral and intravenous administration of [¹⁴C]-gefitinib, excretion of radioactivity by rat, dog and human occurred predominantly via the bile into faeces, with <7% of the dose being eliminated in urine.

4.?In all three species, gefitinib was cleared primarily by metabolism. In rat, morpholine ring oxidation was the major route of metabolism, leading to the formation of M537194 and M608236 as the main biliary metabolites. Morpholine ring oxidation, together with production of M523595 by O-demethylation of the quinazoline moiety, were the predominant pathways in dog, with oxidative defluorination also occurring to a lesser degree.

5.?Pathways in healthy human volunteers were similar to dog, with O-demethylation and morpholine ring oxidation representing the major routes of metabolism.     

Disposition of 3,3′-dichlorobenzidine in the rat

The disposition of the carcinogen 3,3′-dichlorobenzidine (DCB) was studied in the male rat following oral administration. [¹⁴C]DCB was well absorbed by the rat with the maximum plasma radioactivity levels being found within 8 hr after dosing. The radioactivity was well distributed in the tissues 24 hr after administration with the highest levels found in the liver, followed by kidney, lung, and spleen. Repeated administration (six doses) of [¹⁴C]DCB to animals did not result in a substantial accumulation of ¹⁴C in the tissues. The elimination of radioactivity from the plasma, liver, kidney, and lung was biphasic showing an initial rapid decline (half-lives 1.68, 5.78, 7.14, and 3.85 hr, respectively) followed by a slower disappearance phase (half-lives 33.0, 77.0, 138.6, and 43.3 hr, respectively). Approximately half of the total ¹⁴C in the liver and kidney was covalently bound to cellular macromolecules 72 hr after dosing. [¹⁴C]DCB-derived radioactivity was extensively excreted by rats, mainly via the feces. Approximately 23–33% of the administered dose was recovered in the urine and 58–72% in the feces of rats within 96 hr. More than 65% of the administered ¹⁴C was eliminated in the bile of bile duct-cannulated rats within 24 hr after dosing. The radioactivity excreted in the urine and bile was primarily in the form of free (urine 71.2%, bile 25.5%) and conjugated (urine 19.6%, bile 57.9%) metabolites of DCB. Thus DCB is readily absorbed following oral administration, and then metabolized and excreted mainly via the feces.     

Studies on the Metabolism of d-Limonene (p-Mentha-1,8-diene): I. The Absorption,Distribution and Excretion of d-Limonene in Rats

Abstract

1. The absorption, distribution and excretion of d-limonene were investigated in rats using the ¹⁴C-labelled compound.

2. The highest concentration of radioactivity in blood was obtained 2 h after oral administration of [¹⁴C]d-limonene and most occurred in the serum fraction. Radioactivity in the tissues reached maximum 1 or 2 h after administration. Radioactivity in liver, kidney and blood was higher than in other tissues, but was negligible 48 h after administration. An autoradiographic study confirmed these findings of tissue distribution.

3. About 60% of administered radioactivity was recovered from urine, 5% from faeces and 2% from expired CO₂ within 48 h. In bile duct cannulated rats, about 25% of the dose was excreted in bile within 24 h.     

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.     

Studies on Metabolism of Trazodone,I. Metabolic Fate of [14C]Trazodone Hydrochloride in Rats

Abstract

1. One of the main metabolites of [¹⁴C]trazodone hydrochloride by rat liver in vitro is hydroxylated trazodone.

2. [¹⁴C]Trazodone HCI is absorbed very rapidly and the blood level of radioactivity attains a maximum within 15 min after oral administration of 4 mg/kg to rats and thereafter decreases rapidly.

3. Urinary and faecal excretions of radioactivity are 49.0 and 46.1% of the dose respectively, during the first 7 days after ingestion, and biliary excretion is 80.0% in 8 h.

4. After oral administration of [¹⁴C]trazodone HCI to rats the main metabolites in urine and bile are hydroxylated trazodone, β-{3-oxo-s-triazolo[4,3a]-pyridin-2-yl}-propionic acid and their glucuronides.

5. Unchanged and hydroxylated trazodone alone are present in brain of rats after oral administration (20 mg/kg); both compounds in brain decrease with similar half-lives to those in plasma.     

The comparative disposition and metabolism of dolutegravir,a potent HIV-1 integrase inhibitor,in mice,rats, and monkeys

Abstract

1.?Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12?mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28?L/kg, respectively) with terminal elimination half-life approximately 6?h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension.

2.?Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species.

3.?Following oral administration to rats, [¹⁴C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24?h.

4.?The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.     

The fate of N-nitrosodiethanolamine after oral and topical administration to rats

¹⁴C-labelled N-nitrosodiethanolamine ([¹⁴C]NDELA) was given to Osborne-Mendel rats at two dose levels, 0·5 or 50 mg/kg, by oral or topical administration. The excreta and tissues were analysed at various times from 4 hr to 1 wk after administration to determine the distribution of radioactivity. After oral administration, [¹⁴C]NDELA was rapidly absorbed from the gastro-intestinal tract, distributed throughout all organs and tissues, and then excreted, mainly via the kidneys. The tissue concentration reached a peak at 8 hr, but some activity remained after 1 wk. After topical application NDELA was slowly absorbed percutaneously, but once absorbed was distributed as in the orally dosed rats. Metabolic profiles of urine and bile samples from both the orally and topically dosed rats were identical, although the quantities varied. In addition to unchanged NDELA, one metabolite was present. The dose level had little effect on the quantities of unchanged NDELA or the metabolite present.     

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.