The disposition of gemifloxacin, a new fluoroquinolone antibiotic, in rats and dogs.

Gemifloxacin is a fluoroquinolone antibacterial compound with enhanced affinity for bacterial topoisomerase IV and is being developed for the treatment of respiratory and urinary tract infections. The disposition and metabolic fate of this antibiotic was studied in the rat and the dog, the animal species used in its toxicological evaluation. The investigations were carried out following oral and intravenous administration of gemifloxacin mesylate. Gemifloxacin is a racemic compound; therefore, the pharmacokinetics of its individual (+) and (-) enantiomers were characterized using a chiral high-performance liquid chromatography/tandem mass spectrometry assay. In both rat and dog, the pharmacokinetic profiles of the (+) and (-) enantiomers were essentially identical. The enantiomers were rapidly absorbed following oral administration of racemic gemifloxacin mesylate. They distributed rapidly beyond total body water, and their blood clearance values were approximately equal to one quarter of the hepatic blood flow in each species. Terminal phase elimination half-lives were ca. 2 h in the rat and 5 h in the dog. Gemifloxacin was metabolized to a limited extent following oral and intravenous administration of [14C]gemifloxacin mesylate, and all metabolites formed were relatively minor. The principal metabolites formed were the E-isomer (4-6% of dose) and the acyl glucuronide of gemifloxacin (2-6% of dose) in both species and N-acetyl gemifloxacin (2-5% of dose) in the rat. Data obtained following intravenous administration indicated that gemifloxacin-related material is eliminated from the body via urinary excretion, biliary secretion, and gastrointestinal secretion. Material was eliminated approximately equally by the three routes in the dog, whereas a slightly higher proportion of the dose was eliminated in the urine (46%) and a lower proportion in the bile (12%) of rats.

Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans.

Rosiglitazone is a potent peroxisome proliferator-activated receptor gamma agonist that decreases hyperglycemia by reducing insulin resistance in patients with type 2 diabetes mellitus. The disposition of (14)C-labeled rosiglitazone was determined after oral and i.v. dosing of rosiglitazone solution, and the disposition of nonradiolabeled rosiglitazone was determined after oral dosing of tablets in this open-label, three-part, semirandomized, crossover study. The absorption of rosiglitazone was rapid and essentially complete, with absolute bioavailability estimated to be approximately 99% after oral tablet dosing and approximately 95% after oral solution dosing, and clearance was primarily metabolic. The time to maximal concentration of radioactivity and the elimination half-life for two metabolites in plasma were significantly longer than for rosiglitazone itself (4-6 h versus 0. 5-1 h, and ca. 5 days versus 3-7 h). Radioactivity was excreted primarily via the urine ( approximately 65%) and was excreted similarly after oral and i.v. dosing. The major routes of metabolism were N-demethylation and hydroxylation with subsequent conjugation, of which neither was affected by the route of drug administration. The major metabolites, those of intermediate importance, and nearly all of the trace metabolites in humans have been identified previously in preclinical studies. Rosiglitazone was well tolerated in all formulations.

The fate of a thiazolidinedione antidiabetic agent in rat and dog.

1. The fate of [14C]BRL 49653C, a novel thiazolidinedione antidiabetic agent, has been studied following oral administration to the rat and dog. 2. Clearance was almost exclusively by metabolism, with only small amounts of unchanged BRL 49653 being excreted by either species. 3. Phase I metabolism resulted in ring hydroxylation, N-demethylation and oxidative removal of the pyridinylamino function to yield a phenoxyacetic acid derivative. 4. Sulphation of phase I metabolites occurred in both species, but glucuronidation was only observed in the rat. 5. The parent compound was the major circulating component in both species at early times, but at later times sulphate conjugates of phase 1 metabolites were predominant.

Metabolic and pharmacokinetic studies following oral administration of famciclovir to the rat and dog.

1. Drug-related material was well absorbed following oral administration of 14C-famciclovir to the male rat at doses up to 4000 mg/kg and to the male dog at doses up to 250 mg/kg, as judged by the early onset of the peak blood or plasma concentrations of radioactivity (usually < or = 1.5h) and the rapid extensive excretion of radioactivity in the urine (57-76 and 86-89% of dose in rat and dog respectively). 2. Famciclovir underwent extensive first-pass metabolism in both species. In rat, following dosing at 40 mg/kg, famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma (mean 3.5 micrograms/ml) at 0.5 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other major metabolite detected in rat plasma. Cmax values for BRL 42359 (mean 2.2 micrograms/ml) were also achieved at 0.5 h. In dog, extensive conversion of famciclovir to penciclovir, via BRL 42359, also occurred, but its rate of formation from BRL 42359 was somewhat slower than in rat. In dog, following dosing at 25 mg/kg, Cmax values for penciclovir (mean 4.4 micrograms/ml) occurred at 3 h and were lower than the Cmax values for BRL 42359 (mean 10.0 micrograms/ml) which were achieved at 1h. 3. A dose-dependent decrease in the conversion of BRL 42359 to penciclovir occurred in both species, resulting a changes in the ratios of the plasma concentrations of the two metabolites with increasing dose. In rat, the urinary excretion of penciclovir decreased from 36% of dose at 40 mg/kg to 21% at 4000 mg/kg, and was accompanied by a corresponding increase in the urinary excretion of BRL 42359. In dog, a similar decrease in the urinary excretion of penciclovir occurred on increasing the dose of famciclovir from 25 to 250 mg/kg. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. In rat, following dosing at 40 mg/kg, 54 and 22% of dose were recovered in the excreta as penciclovir and BRL 42359 respectively. Corresponding recoveries of the two metabolites in the dog were 34 and 50% of dose. The metabolic fate of famciclovir in these animal species is, therefore, similar to that reported previously in man.

Metabolism and disposition of 14C-granisetron in rat, dog and man after intravenous and oral dosing.

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.

Determination of BRL 46470 in human plasma by high performance liquid chromatography with ultraviolet absorbance detection followed by post-column photochemical reaction and fluorescence detection.

A very sensitive and specific quantitative assay for BRL 46470, a selective 5-HT3 receptor antagonist, in human plasma was developed. The method uses HPLC with serial UV absorbance detection followed by post-column photochemical reaction and fluorescence detection to provide an ultra-sensitive and specific method with a wide quantitative range. The post-column photochemical reaction enhances the very weak native fluorescence of BRL 46470 by a factor of approximately 150. The quantification ranges were determined to be 0.1-1.5 ng ml-1 (fluorescence detection) and 1.5-200 ng ml-1 (UV absorbance detection) for BRL 46470. Results from a 3 d validation at nominal BRL 46470 concentrations of 0.1, 0.4, 1.0 and 1.5 ng ml-1, using post-column photochemical reaction and fluorescence detection, demonstrated precision ranges of 3.4-5.8% (average within-day) and 1.6-5.6% (between-day). The average accuracy ranged from 93.4 to 114.5%. Results from a 3 d validation at nominal BRL 46470 concentrations of 1.5, 4.0, 25 and 200 ng ml-1, using UV absorbance detection, demonstrated precision ranges of 2.0-8.2% (average within-day) and 1.0-3.4% (between-day). The average accuracy ranged from 86.3 to 103.7%. The recovery of BRL 46470 from human plasma was approximately 64%. Assay specificity was confirmed by HPLC-MS.

Metabolic and pharmacokinetic studies following oral administration of 14C-famciclovir to healthy subjects.

1. Following oral administration of 14C-famciclovir (500 mg) to three healthy male subjects, drug-related material was rapidly absorbed as judged by peak plasma concentrations of radioactive material being achieved by 0.75 h (6.7 +/- 0.9 microgram equiv./ml (mean +/- SD). 2. Famciclovir underwent extensive first-pass metabolism and was only detected in the plasma of one subject at low concentrations (0.5 microgram/ml). Famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma of 3.6 +/- 0.7 microgram/ml (0.75 h). The plasma elimination half-life value for penciclovir was 2.1 +/- 0.1 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other relatively major metabolite detected in plasma. Peak plasma concentrations of BRL 42359 (1.0 +/- 0.1 microgram/ml) were achieved at 0.5 h. 3. After 3 days, 73.0 +/- 6.1% of the radioactive dose was excreted in urine, showing that good absorption of drug-related material occurred. Renal excretion was rapid since 60.2 +/- 4.2 and 72.3 +/- 5.7% of the dose was recovered in the urine samples collected up to 6 and 24 h, respectively. A good recovery of the administered radioactive dose was obtained since a further 26.6 +/- 5.1% of the dose was excreted in the faeces over a 72-h period. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. Penciclovir accounted for 59.2 +/- 4.9 and 4.2 +/- 1.4% of the dose in 0-24 h urine and 0-48 h faeces, respectively. Corresponding values for BRL 42359 were 5.0 +/- 0.5 and 17.0 +/- 6.2%, respectively. These metabolites were identified in the biological samples using hplc-ms and ms-ms with thermospray ionization.