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.     

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.     

Pharmacokinetics of NS-105, a novel cognition enhancer. 1st communication: absorption, metabolism and excretion in rats, dogs and monkeys after single administration of 14C-NS-105

The absorption, metabolism and excretion of NS-105 ((+)-5-oxo-D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition enhancer, were studied in rats, dogs and monkeys after intravenous or oral administration of 14C-NS-105. The protein binding of this drug was also investigated in vivo and in vitro. After the intravenous and oral administrations of 14C-NS-105, the unchanged drug accounted for most of the plasma radioactivity in all the species tested. After the intravenous injection, the plasma concentration of NS-105 decreased monoexponentially with respective elimination half-lives of 0.67, 2.1 and 1.3 h for the rats, dogs and monkeys. After the oral administration, the plasma concentration of NS-105 reached a maximum within 1 h, then decreased as in intravenous administration in all the species tested. NS-105 was almost completely absorbed from the small intestine, and first-pass metabolism was very limited. As a result, its systemic availability was high; 97% in the rats, 90% in the dogs and 79% in the monkeys. No significant sex-related differences in the plasma concentration profiles of radioactivity were observed in the rats after the oral administration of 14C-NS-105 (p > 0.05). Food affected the absorption of NS-105. The Cmax and AUC0-infinity of radioactivity concentration were proportional to the dose for 1-100 mg/kg of 14C-NS-105. There were no marked differences between the intravenous and oral routes in the compositions of urinary radioactivity for any of the species tested. In the urine of dogs, LAM-162 (oxidative metabolite with C-N cleavage of the piperidine ring), LAM-79 (metabolite with 4-hydroxylated piperidine ring), LAM-163 (metabolite with 3-hydroxylated piperidine ring) and M1 (not identified) accounted for 20%, 3%, 6% and 1% of the urinary radioactivity, respectively. In the urine of rats and monkeys, LAM-162 and LAM-79 accounted for 1-6% of the urinary radioactivity, but LAM-163 and M1 were not detected. After the intravenous and oral administrations, NS-105 was primarily eliminated by renal excretion in all the species tested, approximately 90% of the dose being excreted unchanged in the urine for rats and monkeys and 60% of it for dogs. Excretions of radioactivity in the bile and exhaled air in rats were less than 1.4% of the dose, and lymphatic absorption of radioactivity was only 0.3% of the dose. The percentage of 14C-NS-105 bound to serum proteins was less than 3.3% in all the animal species tested, including humans.     

Metabolism of 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo [4,3-alpha] [1,4] benzodiazepine, triazolam, a new central depressant. I. Absorption, distribution and excretion in rats, dogs and monkeys.

1. Peak radioactivity in the blood was reached at 30 min after i.p. and 1 h after oral dosing of [14C]triazolam to rats. In dogs, peak blood level was observed at 30 min after oral dosing. 2. Daily dosing of triazolam to male rats for 21 days caused a gradual increase in blood level, with peak at 1 h after dosing. 3. The rate of binding of triazolam plus its metabolites to plasma protein of rats was about 30% at 15 min and 6 h. 4. In rats, the majority of the activity of the intra-intestinally administered [14C]triazolam was found in the small intestines in 6 h. 5. About 58% of the oral dose and 77% of the i.p. dose were recovered in the bile of rats in 48 h after dosing. When the bile from one rat was introduced into the duodenum of a second rat, approximately 37% was recovered in the bile of the second animal in 24 h. 6. In male rats, high radioactivity was seen in the liver, kidneys, adrenals and heart, and low in the CNS. By 96 h after dosing, radioactivity in the liver, blood and kidneys was very low, and was undetectable in other tissues and organs. Radioactivity levels in tissues after daily dosing for 7, 14 and 21 days did not differ appreciably from single administration. 7. In monkeys, activity was high in the liver, kidneys and skin following oral administration and low in the CNS. 8. After oral administration of [14C]triazolam to pregnant rats, the activity in the uterus and placenta was higher than that in the maternal blood. The activity in the foetus was low. 9. In rats given [14C]triazolam orally or i.p., 85% and 12% of the oral dose, and 82% and 14% of the i.p. dose were recovered in the faeces and urine, respectively, in 96 h. The rate of cumulative faecal and urinary excretion after repeated dosing was similar to the single dosing with 80% and 14% of the activity recovered, respectively, in faeces and urine in 6 days. In dogs, 50% of the oral dose was found in the faeces and 40% in the urine. 10. Radioactivity in the milk of rats was maximal at 4 h after oral dosing. It declined to 34% of the peak level 48 h later.     

Pharmacokinetics of 4-acetylaminophenylacetic acid. 1st communication: absorption, distribution, metabolism and excretion in mice, rats, dogs and monkeys after single administration of 14C-labeled compound

Absorption, distribution, metabolism and excretion of 4-acetylaminophenylacetic acid (MS-932) were studied in mice, rats, dogs and monkeys after intravenous or oral administration of 5 or 10 mg/kg of 14C-MS-932. After the intravenous injection of 14C-MS-932, the radioactivity concentrations in the plasma decreased biexponentially. The half-lives of the elimination phase (t1/2, beta) were 2.58 h for mice, 2.35 h for rats, 1.88 h for dogs and 1.24 h for monkeys. After the oral administration of 14C-MS-932, the radioactivity concentrations in the plasma reached maximums between 0.4 and 1.3 h, thereafter decreasing with half-lives similar to those found for the intravenous injection. The systemic availability of this drug was 72-100% in all the species tested. No clear sex-related difference in radioactivity concentrations was found in rat plasma. After both intravenous and oral administrations, in all the species tested, almost all the radioactivity administered was excreted in the urine. Biliary excretion of radioactivity in bile duct-cannulated rats was only 1.42% of the intravenous dose over a 24-h period. Lymphatic absorption of radioactivity was negligible (0.2% of the dose over a 6-h period). After oral administration of 14C-MS-932, the radioactivity concentrations in the rat tissues tested reached maximums within 1 h, decreasing rapidly thereafter similar to the decrease in the concentration in the plasma. Much higher concentrations were present in the kidney and gastro-intestinal tract than in the plasma, whereas the concentrations in the other tissues were lower. Results obtained by whole-body autoradiography were consistent with those obtained for the radioactivity in excised tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of nisoldipine. I. Absorption, concentration in plasma, and excretion after single administration of [14C]nisoldipine in rats, dogs, monkey, and swine

The absorption, disposition and excretion of (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) have been studied following a single administration of the 14C-labelled compound to rats, dogs, monkey and swine via different routes (intravenous, oral, intraduodenal) in the dose range of 0.05-10 mg.kg-1. [14C]nisoldipine was absorbed rapidly and almost completely. Peak concentrations of radioactivity in plasma were reached 0.9 h (rat), 1.4 h (dog), and 3.6 h (monkey) after oral administration with normalized maximum concentrations being in the same range for all three species (0.49-0.79). The radioactivity was eliminated from plasma with half-lives between 42 h and 54 h within an observation period up to 3 days. The contribution of unchanged [14C]nisoldipine to the concentration of total radioactivity in plasma was low after oral administration (between 0.5% (monkey) and 3.4% (dog) in the peak) indicating an extensive presystemic elimination of this compound. The bioavailability was estimated at 3.4% in rats and 11.7% in dogs. [14C]nisoldipine was highly bound to plasma proteins with free fractions of 0.9-2.9%. The excretion of the radioactivity via urine and feces/bile both after oral and intravenous administration of [14C]nisoldipine occurred rapidly and almost completely within 48 h in all species. Very small residues in the body were recovered at the end of the experiments in rats and dogs (less than 1.6% of the dose). The biliary/fecal route of excretion was preferred in rats, dogs and swine, whereas in monkey 76% of the dose was excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate in rats, dogs and monkeys

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) were studied in rats, dogs and monkeys after administration of [14C]-MN-1695. MN-1695 was found to be well absorbed from the small intestine after oral administration in all species examined. Plasma level of unchanged MN-1695 reached a maximum at 1 to 4 h after oral administration of [14C]-MN-1695 in rats, dogs and monkeys. The mean elimination half-life of unchanged MN-1695 from plasma was about 3, 4 and 50 h in rats, dogs and monkeys, respectively. Tissue levels of radioactivity after oral administration of [14C]-MN-1695 in rats indicated that [14C]-MN-1695 was distributed throughout the body and the radioactivity in tissues disappeared with a rate similar to that in plasma. A stomach autoradiogram after intravenous administration of [14C]-MN-1695 in the rat revealed the radioactivity localized in the gastric mucosa where MN-1695 was assumed to exert its pharmacological activity. In pregnant rats, [14C]-MN-1695 was distributed to the fetus with levels similar to maternal blood levels. After oral administration of [14C]-MN-1695 in rats, 39 to 46% of the dose was excreted into the urine and 50 to 63% of the dose into the feces, within 96 h. In dogs, about 40% of the dose was excreted into the urine and about 50% of the dose into the feces, within 6 days after oral administration. In monkeys, within 14 days after oral administration, about 60 and 30% of the dose were excreted into the urine and feces, respectively, and the main excretion route was the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

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.     

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.     

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

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

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, 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.     

Pharmacokinetics of ciprofloxacin. 1st communication: absorption, concentrations in plasma, metabolism and excretion after a single administration of [14C]ciprofloxacin in albino rats and rhesus monkeys

The absorption, disposition, metabolism and excretion of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3- quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) were studied following a single intraduodenal (rat), oral and intravenous (rat, monkey) administration, respectively, in the dose range 5 to 30 mg/kg body weight. Ciprofloxacin was absorbed partially (30 to 40%) in both species. Peak plasma concentrations of radioactivity were measured approximately 1 h (rat) or 2 h (monkey) after oral dosing. Terminal half-lives ranging from 26 to 44 h were determined for the elimination of radioactivity from the plasma (observation time up to 48 h after dosing). Nearly identical concentrations of the unchanged drug and total radioactivity were found during the first 7 or 8 h for the monkey after intravenous injection and for the rat also after oral administration, respectively. After reaching maximum concentration of 0.25 microgram/ml after administration of 5 mg/kg to rats and 0.88 microgram/ml after dosing with 30 mg/kg to a rhesus monkey, the unchanged drug was eliminated from plasma corresponding to half-lives ranging from 3 h (rat) and 4.4 h (monkey). The radioactivity was rapidly and completely excreted in both species. After intravenous administration about 51% (rat) and 61% (monkey), respectively, was excreted via the kidney. After oral dosing renal excretion amounted to 6-14% (rat) and 30% (monkey), respectively. Maximum residues in the body (exclusive gastrointestinal tract) of 1% of dose occurred in both species. In urine and feces of rats predominantly the unchanged drug and a conjugate were detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood level, metabolism and excretion of [14C]-brotizolam in mice

Blood level, metabolite pattern and excretion of [14C]-brotizolam, a hypnotic drug, were studied in mice following oral administration. [14C]-Brotizolam was rapidly absorbed which was indicated by a Tmax of the blood level of 0.5 h. Radioactive compounds were eliminated from the blood with a half-life of 5.6 h. Total excretion of radioactivity, the renal portion of which was 22.4%, was complete after 4 days. [14C]-Brotizolam was almost completely metabolized. Using TLC, HPLC and radioactivity measurement, the main metabolite in bile, urine and plasma was found to be brotizolam hydroxylated at the methyl group. Other major metabolites were brotizolam hydroxylated at the diazepine ring and a combination of both hydroxylations. In the bile, all metabolites were conjugated. The metabolism of brotizolam in mice is similar to that in dogs, monkeys and man but not in rats.     

The pharmacokinetics and disposition of MK-0524, a Prostaglandin D2 receptor 1 antagonist,in rats,dogs and monkeys

MK-0524 is a potent, selective and orally active Prostaglandin D₂ receptor 1 (DP₁) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5?mg/kg), the mean Cl_p was ～2 and ～6?ml/min/kg, the T_1/2 was ～7 and ～13?h and the Vd_ss was ～1 and ～5 L/kg, respectively. In monkeys dosed i.v. at 3?mg/kg, the corresponding values were 8?ml/min/kg, 3?h and 1?L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100?mg/kg), dogs (5?mg/kg) and monkeys (3?mg/kg), the absorption was rapid with the mean C_max occurring between 1 and 4?h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.     

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).     

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.     

Absorption, plasma concentration, and excretion after single administration of 14C-(+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5- nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate hydrochloride in rats and dogs.

The absorption, plasma concentrations, and excretion of a newly synthesized calcium antagonist, TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate hydrochloride, CAS 96515-74-1) were studied following a single oral or intravenous administration of 14C-labelled compound. After oral administration, 14C-TC-81 was rapidly and well absorbed from the gastrointestinal tract. The peak plasma concentrations of radioactivity were observed at 0.5-1 h (rats) and 1-2 h (dogs) h after dosing. The elimination of the radioactivity in plasma was biphasic with a half-life of 3.8-5.2 h (a phase) and 42.9-56.2 h (beta phase) in the rats or 3.2 h (a phase) and 61.5 h (beta phase) in dogs. Maximum plasma concentrations of unchanged drug after oral administration of TC-81 to male rats at the doses of 0.5, 1.0, and 3.0 mg/kg were 1.7, 7.3 and 15.6 ng/ml, respectively. They were attained at 0.5 h after dosing in every dose examined. Plasma levels of unchanged drug declined with a half-life of 0.39-1.15 h. When TC-81 was orally administered to male dogs at the doses of 0.1, 0.2 and 0.5 mg/kg, plasma concentrations of unchanged drug reached the maximum level at 0.5 h after dosing and the values were 0.8, 3.3 and 9.6 ng/ml, respectively. They were eliminated with a half-life of 2.4-2.8 h. The absolute bioavailability of unchanged drug was estimated to be 2.6-7.0% (rats) and 5.3-15.5% (dogs) of the dose.(ABSTRACT TRUNCATED AT 250 WORDS)