Absorption, distribution, metabolism and excretion of bacmecillinam. I. Absorption, distribution, metabolism and excretion of 14C-bacmecillinam following oral administration to rats

The pharmacokinetics of bacmecillinam (KW-1100), a new semisynthetic penicillin, was studied. Plasma levels, tissue distribution, metabolites and urinary and biliary excretion of mecillinam after oral administration of KW-1100 were studied in rats given a dose of 20 mg/kg (as mecillinam). The absorption of 14C-KW-1100 was so rapid that the level in blood was found to reach the peak 30 minutes after administration. 14C-KW-1100 was distributed widely into various tissues and relatively high distribution was noted in liver, kidney, adrenal gland and spleen. No accumulation of 14C-KW-1100 in any tissue was found. It was excreted rapidly from each tissue. Within 24 hours after administration of KW-1100, approximately 86% of the given dose was excreted. And within 72 hours, approximately 97% of the dose was excreted. Excretions in urine and feces within 72 hours after KW-1100 administration were 39.5 and 57.4% of the given dose, respectively. Biliary excretion was 2.0% of the given dose within 24 hours after administration of KW-1100. The major metabolite in the plasma at peak time (30 minutes) was mecillinam (50.5%). The major metabolite in the urine (0 approximately 8 hours) was mecillinam (52.2%), too. The minor metabolites were 5,5-dimethyl-2-(1'-formamidomethyl)-thiazolidine-1',4-dicarboxylat e(M-1), 6-beta-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicilloic acid (M-6) and M-4.     

Metabolism of the antiarrhythmic agent, indecainide, in rats, dogs, and monkeys

The biotransformation of indecainide, a potent new antiarrhythmic agent, has been studied in rats and dogs. Indecainide was excreted in the urine primarily as the unchanged compound. The major urinary metabolite was desisopropyl indecainide which accounted for approximately 5% of the urinary radioactivity in both species. This metabolite was also detected in the plasma of rats, dogs, and monkeys. Peak plasma levels of the amine metabolite were 15 and 19% of the peak plasma levels of indecainide in rats and dogs, respectively. Loss of isopropylamine resulted in the formation of an aldehyde intermediate which was stabilized as the cyclic acylaminocarbinol. An acidic metabolite presumably derived from oxidation of the aldehyde was detected as well as a cyclic imide metabolite. An additional minor metabolite corresponding to N-formyl indecainide was observed in the urine but the mechanism of its formation is unknown.     

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.     

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

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

The absorption,distribution and excretion of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. Oral doses of [¹⁴C]lormetazepam (0.05–0.25mg/kg) were rapidly and almost completely absorbed by female dogs, rabbits, rats and rhesus monkeys. Elimination of ¹⁴C was rapid and similar after oral or i.v. doses.

2. Rats excreted most of the dose in the faeces (76%), whereas dogs, rabbits and monkeys excreted it in the urine (60, 85 and 80% respectively. The urinary excretion half-lives of ¹⁴C from monkeys (c. 10?h), rabbits (c. 12?h), dogs (c. 14?h) and rats (c. 8?h) paralleled the rate of decline of plasma concn. of ¹⁴C.

3. Biliary excretion of lormetazepam and/or its metabolites occurred in rats (83%), dogs (48%) and possibly to a lesser extent in the other two species. Enterohepatic circulation of ¹⁴C in rat was extensive (47%), but not of long duration, and probably occurred in dog and rabbit.

4. Mean peak plasma concn. of ¹⁴C in dogs, rabbits, rats and monkeys of 190, 29, 42 and 280 ng equiv./ml respectively were reached at 1.5, 1, 0.5 and 1?h. A.U.C. values after oral and i.v. doses were similar in dogs, rats and monkeys. In these species, plasma concn. declined biphasically with t_1/2 values of about 15, 14 and 11?h respectively.

5. Concn. of ¹⁴C in rat tissues, particularly in blood cells, liver, kidneys and gut, were several times greater than those in plasma after single or multiple oral doses. Some accumulation in tissues occurred after multiple doses, presumably partly because of accumulation of ¹⁴C in blood cells.

6. Transplacental transfer of ¹⁴C into foetuses of rats or rabbits was low. In rabbits, maternal: foetal concn. ratios ranged between 9 and 26 : 1 after oral or i.v. doses.

7. The excretion (rats and dogs), or plasma ¹⁴C concn.-time profiles (dogs), were not altered during multiple oral doses for 21 days.     

Metabolism, distribution and excretion of a selective N-methyl-D-aspartate receptor antagonist, traxoprodil, in rats and dogs.

Disposition of traxoprodil ({1-[2-hydroxy-2-(4-hydroxy-phenyl)-1-methyl-ethyl]-4-phenyl-piperidin-4-ol}mesylate; TRX), a selective antagonist of the N-methyl-d-aspartate class of glutamate receptors, was investigated in rats and dogs after administration of a single i.v. bolus dose of [(14)C]TRX. Total mean recoveries of the radiocarbon were 92.5 and 88.2% from rats and dogs, respectively. Excretion of radioactivity was rapid and nearly complete within 48 h after dosing in both species. Whole-body autoradioluminography study suggested that TRX radioactivity was retained more by uveal tissues, kidney, and liver than by other tissues. TRX is extensively metabolized in rats and dogs since only 8 to 15% of the administered radioactivity was excreted as unchanged drug in the urine of these species. The metabolic pathways included aromatic hydroxylation at the phenylpiperidinol moiety, hydroxylation at the hydroxyphenyl ring, and O-glucuronidation. There were notable species-related qualitative and quantitative differences in the metabolism of TRX in rats and dogs. The hydroxylation at the 3-position of the phenol ring followed by methylation of the resulting catechol intermediate and subsequent conjugation were identified as the main metabolic pathways in dogs. In contrast, formation of the major metabolites in rats was due to oxidation at the 4'-position of the phenylpiperidinol moiety followed by further oxidation and phase II conjugation. TRX glucuronide conjugate was identified as the major circulating component in rats, whereas the glucuronide and sulfate conjugates of O-methyl catechol metabolite were the major metabolites in dog plasma. The site of conjugation of regioisomeric glucuronides was established from the differences in the collision-induced dissociation product ion spectra of their methylated products.     

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)     

Metabolism of adiphenine. I. Absorption, distribution and excretion in rats and mice

1. The disposition of adiphenine labelled with 14C in two positions has been investigated in rats and mice after i.v. administration, and has been compared with that of the [14C]diethylethanolamine HCl and of the [14C]diphenylacetic acid. 2. Radioactivity in the blood declined in a biphasic manner. Biliary elimination depended upon the 14C-labelled compound administered: less than 5% dose for the diethylethanolamine moiety, 100% dose for the carboxylic moiety. Of the radioactivity appearing in rat bile, less than 1% is associated with unchanged adiphenine. 3. In preliminary metabolic studies, three major metabolites have been identified: diphenylacetic acid, diethylethanolamine and a diphenylacetic acid glucuronide. 4. Uptake by the brain of [14C]adiphenine shortly after dosing is 15 times greater than that of blood. Radioactivity is also found in the hypophysis, the adrenals and melanoid pigments, with a concn. up to 30 times greater than that found in the blood.     

Absorption, distribution, metabolism and excretion of bacmecillinam. III. Absorption, metabolism and excretion of 14C-bacmecillinam following oral administration to dogs

The pharmacokinetics (i.e., blood level, biological half-lives and excretion) of bacmecillinam (KW-1100) was investigated. KW-1100 was orally administered to dogs at the dose of 20 mg/kg (as mecillinam). Biological half-lives (radioactivity) of 14C-KW-1100 in plasma were 1.2 hours (T1/2 alpha) and 52 hours (T1/2 beta). The Cmax and Tmax were 8.4 micrograms/ml and 2 hours. The biological half-life (microbiological activity) of KW-1100 in plasma was 0.9 hour. The Cmax and Tmax were 5.6 micrograms/ml and 1 hour. The urinary and fecal excretion of 14C-KW-1100 were approximately 46% and 49% (0 approximately 72 hours), respectively. The major metabolites in the urine (0 approximately 8 hours) were mecillinam, 5,5-dimethyl-2-(1'-formamidomethyl)-thiazolidine-1',4-dicarboxy lat e (M-1) and 6-beta-[(hexahydro-1 H-azepin-1-yl)-methyleneamino]penicilloic acid (M-6), each distribution ratio of which was 57.2, 24.2 and 12.0% of the total radioactivity in the sample, respectively. The major metabolite in the plasma at peak time (2 hours) was mecillinam (56.2%).     

Pharmacokinetic study of darbepoetin alfa: absorption, distribution, and excretion after a single intravenous and subcutaneous administration to rats

KRN321 is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO, epoetin alfa), and its absorption, distribution, and excretion have been studied after a single intravenous and subcutaneous administration of 125I-KRN321 at a dose of 0.5 microg kg-1 to male rats. The half-lives of immunoreactive radioactivity in the terminal phase after intravenous and subcutaneous administration were 14.05 and 14.36 h, respectively, and the bioavailability rate after subcutaneous administration was 47%. The total radioactivity in tissues was lower than that in the serum in all tissues excluding the thyroid gland and skin at the injection site (subcutaneous administration). The maximum concentrations were observed in the bone marrow or skin at the injection site followed by the thyroid gland, kidneys, adrenal glands, spleen, lungs, stomach and bladder. The radioactivity found in trichloroacetic acid-precipitated fractions suggested that a high-molecular weight compound, unchanged or mixed with endogenous protein, distributed to the tissues after administration. The whole-body autoradiographic findings in both groups were in agreement with the tissue distribution mentioned above. The blood cell uptake of KRN321 was low for both groups. The excretion ratios of radioactivity into urine and faeces up to 168 h were 71.4 and 14.1% after the intravenous administration and 74.9 and 12.0% after the subcutaneous administration. There was no difference in the excretion profile of radioactivity between the two groups.     

Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats,guinea-pigs,beagles and rhesus monkeys

1. The 5-lipoxygenase inhibitor (I), a substituted benzothiazole, is metabolized mainly by glucuronide and/or sulphate conjugation in rat, guinea-pig, beagle and rhesus monkey. Glucuronidation is the major pathway, and sulphation is more extensive in rat and beagle than in guinea-pig and rhesus monkey.

2. After a single oral dosing of ¹⁴C-I (10mg/kg), more than 96% of the dose was excreted in 7 days in all four species, however there is species difference in urinary excretion, which was 2.8 + 0.3% in rat, 46.9.1.6% in guinea-pig, 2.6% in beagle and 68.2% in rhesus monkey.

3. After a single i.v. dose of ¹⁴C-I to bile duct-cannulated rats and guinea pigs, bile was a major route of elimination, and in rats the ratio of glucuronide to sulphate in excreta increased from 0.71.0.01 to 0.93.0.05 as the dose was increased from 0.2 to 20mg/kg.     

Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats, guinea-pigs, beagles and rhesus monkeys

1. The 5-lipoxygenase inhibitor (I), a substituted benzothiazole is metabolized mainly by glucuronide and/or sulphate conjugation in rat, guinea-pig, beagle and rhesus monkey. Glucuronidation is the major pathway, and sulphation is more extensive in rat and beagle than in guinea-pig and rhesus monkey. 2. After a single oral dosing of 14C-I (10 mg/kg), more than 96% of the dose was excreted in 7 days in all four species, however there is species difference in urinary excretion, which was 2.8 +/- 0.3% in rat, 46.9 +/- 1.6% in guinea-pig, 2.6% in beagle and 68.2% in rhesus monkey. 3. After a single i.v. dose of 14C-I to bile duct-cannulated rats and guinea pigs, bile was a major route of elimination, and in rats the ratio of glucuronide to sulphate in excreta increased from 0.71 +/- 0.01 to 0.93 +/- 0.05 as the dose was increased from 0.2 to 20 mg/kg.     

Absorption, distribution and excretion of zenarestat, a new aldose reductase inhibitor, in rats and dogs.

1. The absorption, distribution and excretion of zenarestat have been studied in male rats and dogs after i.v. and oral administration of 14C-zenarestat. 2. The bioavailability of zenarestat was 93% in rats and 65% in dogs. A major proportion of the plasma 14C in rats and dogs was due to unchanged drug. The terminal elimination half-life of zenarestat in plasma was 6 h in rats and dogs. 3. Except for organs associated with absorption and elimination, tissue 14C levels were lower than plasma levels in rats. The distribution to, and elimination from sciatic nerve were slower than those of other tissues. 4. Most of the 14C from 14C-zenarestat administered orally and i.v. to rats and dogs was excreted in the faeces. After i.v. dosing to bile duct-cannulated rats, 96% of the radioactive dose was excreted in the bile.     

Metabolism and excretion of atorvastatin in rats and dogs.

Atorvastatin (AT) is a second-generation potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, clinically approved for lowering plasma cholesterol. Using a mixture of [D(5)/D(0)] AT and/or [(14)C]AT, the metabolic fate and excretion of AT were examined in rats and dogs following single and multiple oral doses. Limited biliary recycling was examined in one dog after a single dose of AT. AT-derived metabolites in bile samples were identified by metabolite screening of the [D(5)/D(0)] AT molecular clusters using tandem mass spectrometry. Bile was a major route of [(14)C] drug-derived excretion, accounting for 73 and 33% of the oral dose in the rat and dog, respectively. The remaining radioactivity was recovered in the feces; only trace amounts were excreted in urine. Radioactive components identified in rat and dog bile were the para- and ortho-hydroxy metabolites, a glucuronide conjugate of ortho-hydroxy AT, and unchanged AT. Two minor radioactive components were identified as beta-oxidation products of AT with one confirmed as a beta-oxidized AT derivative. The reappearance of AT and major metabolites in bile from a dog administered a sample of its previously excreted bile indicated biliary recycling is an important component in AT metabolism. Multiple dose administration in rats did not alter biliary metabolic profiles. Rat and dog plasma profiles after multiple dose administration were similar and showed no additional metabolites not found in bile. Examination of rat and dog bile and plasma indicates that AT primarily undergoes oxidative metabolism.     

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.     

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, ¹⁴C-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–∞ of total radioactivity were 36.2 and 47.1?µg?eq.?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.