ABSTRACT
The in vitro metabolism of ciclesonide, a novel inhaled nonhalogenated glucocorticoid for the treatment of asthma, was compared in cryopreserved hepatocytes from mice, rats, rabbits, dogs, and humans. Incubations of C-ciclesonide with individual hepatocyte suspensions revealed similar metabolite profiles in all 5 in vitro systems used. Ciclesonide was rapidly converted to its active metabolite, desisobutyryl-ciclesonide (des-CIC). Des-CIC was then extensively metabolized to pharmacologically inactive metabolites through oxidation and reduction, followed by glucuronidation. A total of 12 groups of metabolites derived from des-CIC were characterized and identified by liquid chromatography/radioactivity monitor/mass spectrometry. Oxidation occurred on both the cyclohexane ring and the steroid moiety. Hippuric acid formation by cleavage of the cyclohexylmethyl moiety of ciclesonide, followed by aromatization of the cyclohexane ring through multiple steps of hydroxylation, dehydration, and conjugation with glycine, was found in rat, rabbit, and human hepatocyte incubations. The results indicated that ciclesonide and its active metabolite, des-CIC, were extensively metabolized in vitro in animal and human hepatocytes and that the metabolite profiles in mouse, rat, rabbit, and dog hepatocytes were similar to the profiles in human hepatocytes.
Subject(s)
Anti-Allergic Agents/metabolism , Hepatocytes/metabolism , Pregnenediones/metabolism , Animals , Dogs , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred ICR , Rabbits , Rats , Rats, Sprague-Dawley , Species SpecificityABSTRACT
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 (approximately 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.
Subject(s)
Anti-Asthmatic Agents/pharmacokinetics , Pregnenediones/pharmacokinetics , Administration, Oral , Animals , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/blood , Anti-Asthmatic Agents/urine , Area Under Curve , Biological Availability , Biotransformation , Chromatography, Liquid , Dogs , Feces/chemistry , Female , Half-Life , Humans , Injections, Intravenous , Male , Metabolic Clearance Rate , Mice , Pregnenediones/administration & dosage , Pregnenediones/blood , Pregnenediones/urine , Rabbits , Rats , Rats, Wistar , Tandem Mass SpectrometryABSTRACT
M100240, an acetate thioester of MDL 100,173, is a dual angiotensin-converting enzyme/neutral endopeptidase inhibitor currently in Phase II development. M100240 and MDL 100,173 were evaluated in an in vitro cytochrome P450 human hepatocyte model for enzyme induction. Although a dose-dependent CYP3A induction was observed between 10 and 100 microM, at 1 microM-which approaches clinically relevant plasma concentrations in humans-there was no evidence of CYP3A induction. An in vitro reporter gene assay also demonstrated the CYP3A isozyme induction potential of M100240 and MDL 100,173 with an EC(50) approximately 1.5 microM. The present study evaluated the potential for CYP3A enzyme induction in healthy volunteers. In an open-label, single-sequence, replicate-design study using midazolam as a CYP3A probe in 13 healthy volunteers, we found no evidence of clinically relevant CYP3A induction after multiple-dose administration of 50 mg M100240 orally once daily for 15 days. Single and multiple doses of M100240 increased the midazolam AUC(0-24 h) about 1.6-fold compared to baseline, suggesting weak CYP3A inhibition. Concomitant administration of midazolam and M100240 was generally safe and well tolerated. Although in vitro CYP3A induction at exposures in excess of clinically relevant human plasma concentrations has been demonstrated, there is no clinical evidence of CYP3A induction with M100240 administration at proposed therapeutic doses.
