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 4-acetylaminophenylacetic acid. 2nd communication: tissue accumulation and enzyme induction in rats after repeated administration, and placental and milk transfer after single dosing

The absorption, distribution, metabolism and excretion of 14C-labeled 4-acetylaminophenylacetic acid (MS-932) were studied in male rats after administration of an oral dose of 10 mg/kg once a day for 21 days. Comparison with the single dosing showed no marked alterations in absorption, distribution, metabolism and excretion. There were no significant differences in the activities of hepatic aniline hydroxylase and aminopyrine N-demethylase between the MS-932 treated group (10 mg/kg for 8 days) and the 0.5% aqueous sodium carboxymethyl cellulose control group (p greater than 0.05). Placental transfer of radioactivity was studied after single oral administration of 10 mg/kg of 14C-MS-932 to pregnant rats on the 12-13th and 19-20th days of gestation. Radioactivity concentrations were highest in the maternal plasma and lowest in the amniotic fluid and fetus for both middle and late pregnancies. The concentrations in the amniotic fluid and fetus decreased more slowly than did the concentration in the maternal plasma. Excretion of radioactivity to milk was studied after single oral administration of 10 mg/kg of 14C-MS-932 to lactating rats on the 10th day after parturition. Radioactivity concentrations in the rat milk were maximal at 1 h after dosing and were lower than in the maternal plasma at all the sampling times.     

The pharmacokinetics of nitrendipine. II. Distribution to and elimination from organs and tissues of rats and dogs after single or repeated administration of [14C]nitrendipine

[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 male rats, pregnant and lactating female rats, and female dogs intravenously or orally once as well as to male rats repeatedly over a period of 4 weeks (rat 5 (and 10) mg/kg, dog approximately 3 mg/kg). The distribution of radioactivity (unchanged compound and metabolites) was investigated using whole-body autoradiography as well as quantitative measurements of the organ and tissue concentrations of radioactivity after necropsy. [14C]nitrendipine was distributed rapidly and heterogeneously into the organs and tissues of rats. Already 24 h after administration most of the radioactivity had reached the gastro-intestinal (GI) tract via biliary secretion. High concentrations were also detectable in liver and kidneys. The radioactivity was eliminated from the tissues with terminal half-lives lying between 52 (plasma) and 360 h (muscle). Only 0.13% of the administered radioactivity was detectable in the body (excl. GI-tract) after 10 days. In dogs, the distribution pattern was similar to that observed in rats. After 28 daily administrations of [14C]nitrendipine to male rats the plasma and tissue equivalent concentrations were 3 (plasma) to 12 times (adipose tissue) higher than after single administration. The half-lives were increased by 20 to 70%, lying between 2 and 15 days. There were no indications for any specific retention of the radioactivity. The radioactivity from [14C]nitrendipine was secreted into the milk of lactating rats and crossed the placental barrier.(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.     

Pharmacokinetics of NS-105, a novel cognition enhancer. 2nd communication: distribution and transfer into fetus and milk after single administration, and effects of repeated administration on pharmacokinetics and hepatic drug-metabolizing enzyme activities in rats

The tissue distribution and transfer into the fetus and milk of NS-105 ((+)-5-oxo-D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition enhancer, were investigated in rats after single oral administration of 14C-NS-105. The effects of repeated oral administration on the pharmacokinetics of NS-105 and hepatic drug-metabolizing enzyme activities also were investigated in rats. The radioactivity concentration in most tissues of male rats reached a maximum of 0.5 h after the single oral administration of 14C-NS-105, indicating rapid absorption and distribution, 0.5 h after the administration, the highest concentrations were present in the kidney and stomach, and the lowest in the white fat. The concentrations in the remaining tissues were moderately lower than the plasma value. The radioactivity concentrations in all the tissues tested decreased along with the plasma concentration, and were below or near the detection limit 24 h after the administration. Most of the radioactivity in the plasma, liver, kidney and cerebrum was due to unchanged NS-105. The tissue distribution patterns of radioactivity in female (non-pregnant) and pregnant rats after the oral administration of 14C-NS-105 did not differ from the pattern in male rats, revealing neither sex- nor pregnancy-related differences in NS-105 distribution. In pregnant rats, the maximum concentration in the fetus was 66% of that in the maternal plasma. In lactating rats, the radioactivity concentration in the milk was similar to that in the plasma. During and after the repeated oral administration of 14C-NS-105, the plasma concentrations and cumulative urinary and fecal excretions of radioactivity did not change with the number of administrations and were similar to the corresponding values after the single administration. The radioactivity concentrations in most tissues 8 h after the 7th, 14th and 21st administrations were about twice the corresponding values after the single administration, indicating that there is no marked accumulation of radioactivity in the tissues and that a steady state level was reached within 1 week. Repeated oral administration of NS-105 (10 mg/kg) to male rats did not affect hepatic drug-metabolizing enzyme activities.     

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.     

Transplacental and mammary passage of radioactivity in rats treated vaginally and orally with [14C]propranolol

The milk transfer, maternal-fetal distribution, and disposition of the antihypertensive/spermicidal agent propranolol were studied in pregnant and lactating rats. Single doses (10 mg/kg) of an aqueous solution of [14C]propranolol were administered either orally (po) or intravaginally (ivg) on gestational d 15, or on postpartum d 7-10. Upon ivg administration, [14C]propranolol was quickly transferred to systemic circulation and the mean blood [14C] concentrations were significantly greater during the first 0.25-2 h than in po dosed counterparts. About 98% of the ivg applied dose was absorbed after 6 h in gravid rats, and the combined 6-h excretions of radioactivity in the urine (ivg = 24.6%; po = 22.9%) and feces (ivg = 16.8%; po = 14.6%) were equivalent in both groups. At the end of 6 h, the levels of [14C] in the urinary bladder, adrenal, uterus, ovary, spleen, skeletal muscle, brain, heart, lung and fat were significantly higher in ivg treated rats than po dosed animals. Compared with the maternal plasma (ivg = 0.76; po = 0.88 microgram/ml), the mean concentrations of [14C] in the placentas were similar in both groups, while the amounts of [14C] were three to five times lower in the amniotic fluids and the fetuses of both po and ivg treated dams. In lactating rats, over 99% of the administered radioactivity was absorbed from the vagina within 6 h. The blood concentrations of [14C] were significantly elevated at 0.5 and 1 h in the per vaginam treated animals, and afterward the disappearance rate of [14C] followed a similar course in both groups. Following ivg application, the milk radioactivity peaked at 0.5 h and declined rapidly. However, the appearance of [14C] in milk was rather slow after oral dosing: the milk [14C] peaked between 2 and 3 h posttreatment and remained steady thereafter. The milk to blood (M/B) [14C] concentration ratios were markedly greater during 0.5 to 1 h in the ivg group than in their po dosed counterparts. At 6 h, the [14C] levels in the whole blood, plasma, milk, and mammary gland were virtually equivalent in the ivg and po treated females. Comparison of the areas under the milk [14C] concentration-time curves (AUCs) indicated that the milk availability of [14C] was about 31% more in dams dosed vaginally. These data suggest that route of administration alters the disposition and milk excretion of [14C]propranolol-derived radioactivity in pregnant and lactating 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.     

Pharmacokinetics of the new pyrimidine derivative NS-7, a novel Na+/Ca2+ channel blocker. 2nd communication: tissue distributions, placental transfer and milk secretion of radioactivity after a single intravenous 14C-NS-7 injection to rats

Tissue distribution, placental transfer and secretion of radioactivity in milk were studied after a single intravenous administration of 0.2 mg/kg of 14C-NS-7 (4-(fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride, CAS 178429-67-9), a novel Na+/Ca2+ channel blocker, to rats. Except for white fat in male and female rats, tissue radioactivity concentrations 5 min after administration were 2 to 100 times the plasma values, evidence that the drug is widely distributed throughout the body. Five minutes after administration the highest concentration was in the lung followed in order by the adrenal gland, kidney and thyroid gland. Concentrations in the cerebral cortex, striatum and cerebellum, the target organs of NS-7, were similar and 10 to 18 times the plasma concentrations in the male and female rats. Radioactivity concentrations in the lungs decreased rapidly. The pancreas had the highest concentration 2 h after administration. Concentrations decreased in all the tissues examined as the plasma concentration decreased. Maternal and fetal tissue radioactivity concentrations were determined after intravenous injection of 14C-NS-7 to pregnant rats on the 18th day of gestation. Radioactivity was well and rapidly distributed to the maternal tissues, and concentrations in all the tissues tested were higher than the plasma concentrations. In the amniotic fluid, however, the concentration was lower than in the plasma. In all the fetal tissues tested, radioactivity reached a maximum 1 h after administration. The respective fetal blood and whole body concentrations were 2 to 6 and 11 to 13 times the maternal plasma concentration. Of the fetal tissues tested the liver had the highest radioactivity. Decreases in fetal tissue radioactivity concentrations paralleled the decrease in the maternal plasma. More than 90% of the radioactivity present in the placenta and fetal whole body 1 and 24 h after administration was due to the unchanged drug. After intravenous injection of 14C-NS-7 (0.2 mg/kg) to lactating rats on the 10-14th day after parturition, radioactivity was excreted rapidly into the milk, reaching a maximum that was 4 to 6 times the plasma value 1 h after injection.     

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.     

Pharmacokinetics of nimodipine. I. Communication: absorption, concentration in plasma and excretion after single administration of [14C]nimodipine in rat, dog and monkey

Studies on absorption, plasma concentrations and excretion with (+/-)isopropyl-2-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nimodipine, Bay e 9736, Nimotop) have been conducted in rat, dog and monkey using the carbon-14-labelled substance and a wide range of doses (0.05-10 mg/kg) administered via different routes (intravenous, oral, intraduodenal). Nimodipine was well absorbed in all species. Peak plasma concentrations of radioactivity were determined 28-40 min (male rat), 60 min (female rat), about 3 h (dog) and 7 h (monkey) after administration. Dependent on the observation period (24-216 h) terminal half-lives for the elimination of radioactivity from plasma ranging between 4.6 h (female rat) and 157 h (dog) were observed. Comparing the AUC, the concentration of unchanged [14C]nimodipine in plasma represented only a small (maximally 37% in dogs after i.v. dose) to negligible (about 1%, monkey after oral dosing) part of the total radioactivity. Excretion of radioactivity via feces and urine was rapid in all species after both oral and intravenous dosing. Fecal (biliary) excretion was the major excretory route in rat and dog. The monkeys excreted about 40 to 50% via the urine. Residues in the body never exceeded 1.5% of the dose. [14C]nimodipine and/or its radiolabelled metabolites were secreted in milk of orally dosed lactating rats. Binding of [14C]nimodipine to plasma proteins of rat and dog was about 97%.     

Distribution to and elimination from tissues following a single or repeated administration of 14C-(+-)-3-(benzyl-methylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedica rbo xylate hydrochloride in rats.

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) was administered to adult male rats, pregnant and lactating rats with a single oral dose or with repeated doses of 0.3 mg/kg for 2 weeks. The distribution to tissues, placental transfer and secretion of the radioactive drug into milk was studied using whole body autoradiography methods and quantitative determination of total radioactivity after autopsy. 14C-TC-81 was distributed rapidly but disproportionately to the tissues after single administration. The highest concentration of radioactivity was observed in the liver. The radioactivity in the various tissues declined slowly comparing to the plasma but at 96 h after dosing the radioactivity was detected only in the liver. The radioactivity penetrated the blood-placental barrier to a low extent after oral administration of 14C-TC-81 to pregnant rats. When 14C-TC-81 was administered to lactating rats, the radioactivity was secreted into the milk with the maximum concentration of radioactivity, 86% of the corresponding plasma concentration. Following 14-day oral treatments of male rats the equivalent concentration in the plasma was increased 1.5 fold as compared to the single treatment. In all tissues, the AUC0-24 h after 1, 7, and 14 days treatment were gradually increased, but these increases were almost the same as or even less than the rise observed in the plasma. After the last dosing, the radioactivity declined slowly with time in most of the tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nadolol: placental transfer and excretion in the milk of rats.

The transfer of radioactivity from maternal blood to the fetuses of pregnant rats was studied after they had been dosed orally with 100 mg/kg of [¹⁴C]nadolol (2,3-cis-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol) on Days 12, 15, and 18 of gestation. On Day 12 of gestation, during the time of organogenesis, radioactivity crossed the placental barrier to the fetuses; however, the extent of this transfer was significantly reduced on Days 15 and 18 of gestation. The excretion of radioactivity was studied in the milk of lactating rats that had been given oral 100-mg/kg doses of [¹⁴C]nadolol. Twelve or 30 hr after the dams had been dosed, radioactivity was presentin greater concentrations in milk than it was in either blood or plasma. The amount of radioactivity found in the pups that had been allowed to suckle during the intervals of 0 to 6 and 12 to 24 hr after the dams had been dosed was, for both intervals, an average of 0.041% of the dose.     

Pharmacokinetics and disposition of DY-9760e, a novel calmodulin antagonist, in rats and monkeys

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, CAS 162496-41-5) is a novel calmodulin antagonist that is being evaluated for the treatment of ischemia. The objective of this study was to characterize the pharmacokinetics and disposition of DY-9760e in rats and monkeys. After a 6 h continuous infusion at 1 mg/kg/h to male rats, the plasma concentration of unchanged DY-9760, as the anhydrous free base of DY-9760e, declined with a terminal half-life of 3.0 h. In monkeys, the plasma concentration of DY-9760 following a 4 h continuous infusion at 1 mg/kg/h declined with a terminal half-life of 3.8 h. Total clearance was 18.3 ml/min/kg in rats and 16.7 ml/min/kg in monkeys. The pharmacokinetics of DY-9760e was linear within a dose range from 1 mg/kg to 16 mg/kg in monkeys. After intravenous bolus administration of 14C-DY-9760e to rats, the radioactivity was widely distributed throughout the body except for the brain and testis. In the brain, which is the target organ of this compound, the concentrations of unchanged DY-9760 in rats were much lower than the corresponding plasma concentrations. These results indicated that the permeability of DY-9760 into the brain was restricted. In contrast, the brain concentrations of the N-dealkylated metabolite DY-9836 were approximately 2- to 3-fold higher than those observed in the plasma. The administered radioactivity was excreted mostly in the feces (95.2% in rats, 83.6% in monkeys), and the biliary excretion of the radioactivity in bile duct-cannulated rats was 86.2% within 48 h, part of which (11.1%) was re-absorbed. The urinary excretion of unchanged DY-9760 was less than 0.5% in both species. The metabolic profile characterized by thin-layer chromatography demonstrated that most of the radioactivity in the urine and bile referred to many polar metabolites. These results indicate that DY-9760e is eliminated mainly through hepatic metabolic clearance in both rats and monkeys.     

Pharmacokinetics of acarbose. Part II: Distribution to and elimination from tissues and organs following single or repeated administration of [14C]acarbose to rats and dogs

Acarbose (O-4,6-dideoxy-4-[[1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)-2-cyclohexen-1-yl]amino]-alpha-D-glucopyranosyl- (1----4)-O-alpha-D-glucopyranosyl-(1----4)-D-glucopyranose, Bay g 5421) labelled with 14C was administered to male rats, pregnant and lactating rats as well as to female dogs with single intravenous or oral doses (2 or 4 mg.kg-1) and with repeated oral doses of 2 mg.kg-1 to male rats for 3 weeks. The distribution of radioactivity to organs and tissues, the placental transfer and the secretion into milk was studied using whole-body autoradiographic methods and/or quantitative determination of total radioactivity after autopsy. Unchanged [14C]acarbose was distributed predominantly in the extracellular space, as observed after intravenous dosing to rats. According to the main excretion route, high concentrations were found in kidneys and urine and additionally in blood, lung, and connective tissue or interstitial space. The permeability of the blood/brain barrier for [14C]acarbose and/or its metabolites was very low. No indication was found for distinct differences in the distribution patterns in rats and dogs after intravenous and also in dogs after oral administration. In contrast, in rats after oral dosing the distribution pattern of radioactivity was different with relatively high concentrations in liver, kidney, adrenal gland, spleen, and intestinal mucosa. Due to the slow absorption of the microbial degradation products of [14C]acarbose from the intestine maximum concentrations in the different tissues were reached 8-24 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Disposition and metabolism of [14C]sparfloxacin in the rat.

Disposition and metabolism of [carbonyl-14C]sparfloxacin SPFX, 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, AT-4140; CAS 110871-86-8), a novel antimicrobial quinolone, were studied in rats mainly after oral administration at 10 mg/kg. SPFX was absorbed from the whole area of small intestine as shown by the loop method. The extent of absorption was around 70% when estimated by AUC, urinary excretion and biliary excretion. Plasma level of radioactivity reached Cmax of 1.32 micrograms eq/ml within 1 h after oral administration and decreased with a half-life of about 4 h. Higher levels of radioactivity than that in plasma were seen in kidney, liver, submaxillary gland, lung, trachea and many other tissues and lower levels, in eye ball, brain and some others. Most tissue levels decreased with time essentially in parallel with plasma level. In pregnant rats, levels of fetal radioactivity amounted to about 60% of maternal plasma level. In lactating rats, milk was found to contain radioactivity several times as high as plasma level, which decreased with a similar half-life. SPFX was bound to plasma protein, mainly to albumin, at about 40%. Unchanged SPFX and its glucuronide were found in the plasma, milk, bile and urine. Within 48 h, about half of the dosed radioactivity was excreted in the bile, and part of which was re-absorbed. Within 96 h, about 20 and 80% of dose were found in the urine and feces, respectively.     

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 14C-pilocarpine following oral administration to rats

The absorption, distribution and excretion of pilocarpine (CAS 92-13-7) were studied after single oral doses of 14C-pilocarpine hydrochloride (CAS 54-71-7) to the Sprague-Dawley rat, administered in aqueous solution mainly at a dose level of 0.3 mg/kg. Rats also received single intravenous doses at 0.3 mg/kg so as to compare 14C pharmacokinetics and excretion. The oral 14C-dose was rapidly and almost completely absorbed from the duodenum and small intestine within 30 min in the male rat and 14C concentrations in plasma declined biexponentially with a terminal half-life of about 9 h. Over the oral dosage range studied, i.e. 0.1-1.0 mg/kg, there was no evidence of significant non-proportionality for Cmax of 14C, whereas there was some such evidence for AUG24. Tissue 14C concentrations in male and pregnant female (Day 18) rats peaked at 0.5 h and mostly declined in parallel with those in the plasma. Excluding tissues concerned with drug absorption and elimination, 14C concentrations in most tissues were similar to, or lower than, those in the plasma. The extent of placental transfer of 14C was small and less than 0.09% of a maternal dose reached a foetus. 14C diffused into maternal milk at concentrations similar to those in the plasma. The 14C-dose was rapidly excreted in male rats, mostly in the urine (about 80%) during 6 h post dose. Recoveries of 14C in mass balance (excretion) studies were in the range 96-100%. There were no apparent gender differences in the disposition of 14C-pilocarpine in the rat.     

Absorption, distribution, metabolism, and elimination of 8-2 fluorotelomer alcohol in the rat.

The absorption, distribution, metabolism, and elimination of [3-14C] 8-2 fluorotelomer alcohol (8-2 FTOH, C7F1514CF2CH2CH2OH) following a single oral dose at 5 and 125 mg/kg in male and female rats have been determined. Following oral dosing, the maximum concentration of 8-2 FTOH in plasma occurred by 1 h postdose and cleared rapidly with a half-life of less than 5 h. The internal dose to 8-2 FTOH, as measured by area under the concentration-time curve to infinity, was similar for male and female rats and was observed to increase in a dose-dependent fashion. The majority of the 14C 8-2 FTOH (> 70%) was excreted in feces, and 37-55% was identified as parent. Less than 4% of the administered dose was excreted in urine, which contained low concentrations of perfluorooctanoate (approximately 1% of total 14C). Metabolites identified in bile were principally composed of glucuronide and glutathione conjugates, and perfluorohexanoate was identified in excreta and plasma, demonstrating the metabolism of the parent FTOH by sequential removal of multiple CF2 groups. At 7 days postdose, 4-7% of the administered radioactivity was present in tissues, and for the majority, 14C concentrations were greater than whole blood with the highest concentration in fat, liver, thyroid, and adrenals. Distribution and excretion of a single 125-mg/kg [3-14C] 8-2 FTOH dermal dose following a 6-h exposure in rats was also determined. The majority of the dermal dose either volatilized from the skin (37%) or was removed by washing (29%). Following a 6-h dermal exposure and a 7-day collection period, excretion of total radioactivity via urine (< 0.1%) and feces (< 0.2%) was minor, and radioactivity concentrations in most tissues were below the limit of detection. Systemic availability of 8-2 FTOH following dermal exposure was negligible.