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Ciclesonide Disposition and Metabolism: Pharmacokinetics, Metabolism, and Excretion in the Mouse, Rat, Rabbit, and Dog

Guo, Zuyu1*; Gu, Zheming2; Howell, Stanley R1; Chen, Kelly1; Rohatagi, Shashank1; Cai, Lining2; Wu, Jinn2; Stuhler, John3

doi: 10.1097/01.mjt.0000209688.52571.81
Original Article

The pharmacokinetics, metabolism, and excretion of ciclesonide, a novel and effective inhaled glucocorticoid for the treatment of asthma, were investigated after intravenous and oral administration of 14C-ciclesonide in the mouse, rat, rabbit, and dog. The pharmacokinetics of ciclesonide in all animal species were characterized by a low oral bioavailability (∼6% or less), a high clearance, and a large volume of distribution. The apparent terminal half-life of ciclesonide was short; the apparent terminal half-life of the active desisobutyryl-ciclesonide metabolite (des-CIC or M1) was longer and ranged from 2.4 to 6.9 hours in the 4 species. Metabolites derived from ciclesonide in serum (or plasma) and excreta samples from the 4 animal species were profiled and identified by LC/RAM/MS (liquid chromatography/radioactivity monitor/mass spectrometry). Ciclesonide was extensively metabolized to yield des-CIC, which was further metabolized to primarily yield hippuric acid and hydroxylated metabolites, namely, isomers of cyclohexane-monohydroxylated des-CIC and B-ring-monohydroxylated des-CIC. Greater than 90% of intravenous and oral 14C-ciclesonide doses were recovered in all species; the main elimination route was fecal/biliary. A comparison of in vitro and in vivo metabolite profiles between mice, rats, rabbits, and dogs with those from humans indicated that metabolic pathways for ciclesonide were qualitatively similar in humans and in the 4 animal species.

1Global Metabolism and Pharmacokinetics, Sanofi-aventis, Bridgewater, NJ; 2XenoBiotic Laboratories Inc., Plainsboro, NJ; and 3DMPK, Quintiles Inc., Kansas City, Kanas, MO.

*Address for correspondence: Global Metabolism and Pharmacokinetics, Sanofi-aventis, Bridgewater, NJ. E-mail:

© 2006 Lippincott Williams & Wilkins, Inc.