Abstract
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 andN-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.
Footnotes
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Send reprint requests to: Mr. Jay V. Ramji, Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Hertfordshire, AL6 9AR, UK. E-mail:Jayant_Ramji{at}sbphrd.com
- Abbreviations used are::
- SB
- SmithKline Beecham
- HPLC
- high-pressure liquid chromatography
- LSC
- liquid scintillation counting
- MS
- mass spectrometry
- fb
- free base
- G.I. tract
- gastrointestinal tract
- AUC(0–t) area under the plasma concentration-time curve to the last quantifiable data point
- AUC(t–inf), area under the plasma concentration-time curve from the last quantifiable data point to infinity
- AUC(0–inf)
- area under the plasma concentration-time curve to infinity
- AUMC(0–inf)
- area under the moment curve to infinity
- Vss
- volume of distribution at steady state
- Received September 22, 2000.
- Accepted December 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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