Summary
Ciclesonide, a novel inhaled corticosteroid, is currently being developed for the treatment of asthma. Here, the enzymes catalysing the human hepatic metabolism of ciclesonide were investigated. When incubated with human liver microsomes (HLM), [14C]ciclesonide was first metabolised to the active metabolite Ml (des-isobutyryl-ciclesonide, des-CIC) and to at least two additional metabolites, M2 and M3. M3 comprises a ‘family’ of structurally similar metabolites that are inactive. 16-Hydroxyprednisolone was also formed in microsomal incubations of [14C]des-CIC, but at approximately one-tenth the amount of both M2 and M3. bis-p-Nitrophenylphosphate and SKF 525-A respectively inhibited des-CIC formation from [14C]ciclesonide by 82% and 49% and M2/M3 formation by 82–84% and 87–89%. Regression analysis showed significant negative correlations (r=−0.96, −0.79 and −0.71, respectively) of M2 formation with CYP3A4/5, CYP2B6 and CYP2C8 activities; M3 formation significantly correlated with CYP4A9/11 (r=0.47). Troleandomycin and diethyldithiocarbamate inhibited M2 and M3 formation by 85% and 45%, respectively. Sulphaphenazole and quinidine had no inhibitory effects. CYP3A4 Supersomes® catalysed notable formation of both M2 and M3 from [14C]des-CIC; CYP2C8 and CYP2D6, but not CYP4A11 formed smaller amounts. It is concluded that the human hepatic metabolism of ciclesonide is primarily catalysed by one or more esterases and, subsequently, by CYP3A4.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bertz R.J., Granneman G.R. (1997): Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin. Pharmacokinet., 32, 210–258.
Lin J.H., Lu A.Y.H. (1998): Inhibition and induction of cytochrome P450 and clinical implications. Clin. Pharmacokinet., 35, 361–390.
Yao C, Levy R.H. (2002): Inhibition-based metabolic drug-drug interactions: Predictions from in vitro data. J. Pharm. Sei., 91, 1923–1935.
Nelson D.R., Koymans L., Kamataki T., Stegeman J.J., Feyereisen R., Waxman D.J., Waterman M.R., Gotoh O., Coon M.J., Estabrook R.W., Gunsalus I.C., Nebert D.W. (1996): P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 6, 1–42.
Tucker G.T., Houston J.B., Huang S.-M. (2001): Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential—toward a consensus. Pharm. Res., 18, 1071–1080.
Bjomsson T.D., Callaghan J.T., Einolf HJ., Fischer V., Gan L., Grimm S., Kao J., King S.P., Miwa G., Ni L., Kumar G., McLeod J., Obach R.S., Roberts S., Roe A., Shah A., Snikeris F., Sullivan J.T., Tweedie D., Vega J.M., Walsh J., Wrighton S.A. (2003): The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab. Dispos., 31, 815–832.
Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. (1951): Protein measurement with the folin phenol reagent. J. Biol. Chem., 193, 265–275.
Rutten A.A.J.J.L., Falke H.E., Catsburg J.F., Topp R., Blaauboer B.J., Van Holsteijn I., Doom L., Van LeeuwenF.X.R. (1987): Interlaboratory comparison of total cytochrome P-450 and protein determinations in rat liver microsomes. Reinvestigation of assay conditions. Arch. Toxicol., 61, 27–33.
Clarke S.E. (1998): In vitro assessment of human cytochrome P450. Xenobiotica, 28, 1167–1202.
Miners J.O., Smith K.J., Robson R.A., McManus M.E., Veronese M.E., Birkett D.J. (1988): Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations. Biochem. Pharmacol., 37, 1137–1144.
Kronbach T., Mathys D., Gut J., Catin T., Meyer U.A. (1987): High-performance liquid chromatographic assays for bufuralol 1′-hydroxylase, debrisoquine 4-hydroxylase, and dextromethorphan O-demethylase in microsomes and purified cytochrome P-450 isozymes of human liver. Anal. Biochem., 162, 24–32.
Sonderfan A.J., Arlotto M.P., Dutton D.R., McMillen S.K., Parkinson A. (1987): Regulation of testosterone hydroxylation by rat liver microsomal cytochrome P-450. Arch. Biochem. Biophys., 255,27–41.
Parker G.L., Orton T.C. (1980): Induction by oxyisobutyrates of hepatic and kidney microsomal cytochrome P-450 with specificity towards hydroxylation of fatty acids. In: Gustafsson J., Carlstedt-Duke J., Mode A., Rafter J. (eds). Biochemistry, Biophysics and Regulation of Cytochrome P-450. Amsterdam: Elsevier/North-Holland Biomedical Press, 373–377.
Guo Z., Zhou X., Nave R., Liu D.W., Feng H., Wu J., Howell S.R., King S.P. (2005): Comparative in vitro metabolism of14C-ciclesonide in hepatocytes from the mouse, rat, rabbit, dog and human. Submitted to Xenobiotica.
Clarke S.E., Jones B.C. (2002): Human cytochromes P450 and their role in metabolism-based drug-drug interactions. In: Rodrigues A.D. (ed). Drug-Drug Interactions New York and Basel: Marcel Dekker, 55–88.
Nave R., Drollman A., Steinijans V.W., Zech K., Bethke T.D. (2005): Lack of pharmacokinetic drug-drug interaction between ciclesonide and erythromycin. Int. J. Clin. Pharmacol. Ther., 43, 264–270.
LeBouef E., Grech-Bélanger O. (1987): Deacetylation of diltiazem by rat liver. Drug Metab. Dispos., 15, 122–126.
Ono S., Hatanaka T., Hotta H., Satoh T., Gonzalez F.J., Tsutsui M. (1996): Specificity of substrate and inhibitor probes for cytochrome P450s: evaluation of in vitro metabolism using cDNA-expressed human P450s and human liver microsomes. Xenobiotica, 26, 681–693.
Mutch E., Nave R., Zech K., Williams F.M. (2003): Esterases involved in the hydrolysis of ciclesonide in human tissues. Eur. Respir. J., 22 [Suppl.45], P1749.
Ong C.-E., Coulter, S., Birkert, D.J., Bhasker C.R., Miners, J.O. (2000): The xenobiotic inhibitor profile of cytochrome P4502C8. Br. J. Clin. Pharmacol., 50, 573–580.
Jönsson G., Ström A., Andersson P. (1995): Budesonide is metabolised by cytochrome P450 3A (CYP3A) enzymes in human liver. Drug Metab Dispos., 23, 137–142.
Chu V., Zeng Z., Pan J., Wei Y.-Y. V., Rao Z., Chen J., King S.P. (2004) In vitro assessment of cytochrome P450 metabolic drug-drug interaction potential of ciclesonide. Drug Metab. Rev., 36 [Suppl. 1], 276.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Peet, C.F., Enos, T., Nave, R. et al. Identification of enzymes involved in Phase I metabolism of ciclesonide by human liver microsomes. European Journal of Drug Metabolism and Pharmacokinetics 30, 275–286 (2005). https://doi.org/10.1007/BF03190632
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03190632