Animal pharmacokinetics and interspecies scaling of Ro 25-6833 and related (lactamylvinyl)cephalosporins

Journal of Pharmaceutical Sciences
W RichterT Lavé

Abstract

From a series of six (lactamylvinyl)cephalosporins, candidates for clinical evaluation were selected on the basis of their kinetic profile in animals and predicted pharmacokinetics in man. Exploratory pharmacokinetic studies with Ro 25-6833 and five related cephalosporins were performed following intravenous administration to rats, dogs, and cynomolgus monkeys. All compounds were characterized by a high protein binding in rat, monkey, and human plasma (unbound fraction < or = 5%), whereas in dog plasma, protein binding was markedly lower. Accordingly, for most compounds, clearance was highest in dogs, and lowest in monkeys. Comparison of the renal clearance of unbound drug with creatinine clearance suggests a renal elimination of Ro 25-6833 by glomerular filtration in both rats and dogs (urinary excretion in monkey was not determined due to drug instability in monkey urine). All other compounds showed different renal excretion mechanisms in rats and dogs, thus making the validity of allometric scaling questionable. Unbound clearances in man were predicted by allometric scaling (Ro 25-6833 only) and by a correlation analysis of cephalosporin pharmacokinetics in monkey and man. Limitations of both methods are discussed. When Ro 2...Continue Reading

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Citations

Dec 12, 2003·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·K WaltonA G Renwick
Dec 21, 2006·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·T ShibayamaT Ikeda
Nov 16, 2002·Journal of Pharmaceutical Sciences·Toshihiro WajimaTakayoshi Oguma
Mar 1, 2005·Journal of Pharmaceutical Sciences·Iftekhar Mahmood
Jul 13, 2002·Journal of Pharmaceutical Sciences·Iftekhar Mahmood, Chandra Sahajwalla
Jul 20, 2007·The Journal of Pharmacy and Pharmacology·Urban Fagerholm
May 12, 2004·Regulatory Toxicology and Pharmacology : RTP·K SchneiderM Hassauer
Sep 7, 2011·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yeamin HuhMeihau Rose Feng
Jun 17, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Huadong Tang, Michael Mayersohn

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