LC-HRMS/MS study of the prodrug ciclesonide and its active metabolite desisobutyryl-ciclesonide in plasma after an inhalative administration to horses for doping control purposes.
Abstract: Ciclesonide (CIC) is the first inhaled highly potent corticosteroid that does not cause any cortisol suppression. It has been developed for the treatment of asthma in human and more recently in equine. CIC is the active compound of Aservo® EquiHaler® (Boehringer Ingelheim Vetmedica GmbH), the pre-filled inhaler generating a medicated mist based on Soft Mist™ technology. This prodrug is rapidly converted to desisobutyryl-ciclesonide (des-CIC), the main pharmacologically active compound. Due to its anti-inflammatory properties, CIC is prohibited for use in horse competitions. To set up an appropriate control, the determination of detection times and screening limits are required. Therefore, a highly sensitive analytical method based on supported liquid extraction (SLE) combined with liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) was developed to detect CIC and its active metabolite des-CIC in plasma. The lower limit of detection of CIC and des-CIC was approximately 1 pg/ml in plasma. After a pilot study conducted on a single horse at the recommended dose (eight actuations twice daily corresponding to 5.5 mg/day for the first 5 days, followed by 12 actuations once daily corresponding to 4.1 mg/day in the last 5 days), the same protocol was applied in the main study using six horses. In all horses, CIC and des-CIC levels were less than 5 and 10 pg/ml, respectively, at 36 h after the end of the administration. The outcome of this risk assessment study should be useful to draw any recommendations for horse competitions.
© 2021 John Wiley & Sons, Ltd.
Publication Date: 2021-10-30 PubMed ID: 34634175DOI: 10.1002/dta.3174Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The study explores the use of a potent corticosteroid, ciclesonide (CIC), in treating equine asthma and the method of detecting it in horse plasma for doping control purposes after the inhalation of the drug.
Objective of the Research
The researchers’ main aim is to identify the concentration of CIC and its active metabolite, desisobutyryl-ciclesonide (CIC-des), in horse plasma. They also want to establish a detection time and screening limits for the presence of CIC in the horse’s body to put up a proper control system against its use in horse competitions due to its powerful anti-inflammatory properties.
Methodology
- A highly sensitive analytical method was constructed to detect CIC and des-CIC. This was a combination of supported liquid extraction and liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS).
- The experiment was trialed on a single horse. The horse was given the recommended dosage of the medication: eight actuations twice a day (equivalent to 5.5mg per day) for the first five days, then 12 actuations once a day (equivalent to 4.1mg/day) for the last five days.
- The same protocol was then applied to six more horses.
Results and Findings
- Additionally, the lower limit of detection for CIC and des-CIC was approximately 1 pg/ml in horse plasma. After inhalation, the prodrug CIC was rapidly converted into des-CIC, the primary pharmacologically active compound.
- In all horses, CIC levels and des-CIC levels were below the specified 5 and 10 pg/ml, respectively, 36 hours after the last dosage.
Significance of the Research
- The findings from this risk assessment study can give direction for implementing regulations in horse competitions. This study’s results will be beneficial in preventing the misuse of the drug for enhanced performance in horse competitions, protecting the integrity of the sports industry.
- Moreover, it highlights the efficacy of the LC-HRMS/MS method in detecting minimal traces of the corticosteroid, CIC and its metabolite in horse plasma, which can help develop optimal detection techniques.
Cite This Article
APA
Trevisiol S, Moulard Y, Kaabia Z, Delcourt V, Loup B, Garcia P, Boyer S, Dauriac K, Groseille G, Rouger S, Narbe R, Popot MA, Bailly-Chouriberry L.
(2021).
LC-HRMS/MS study of the prodrug ciclesonide and its active metabolite desisobutyryl-ciclesonide in plasma after an inhalative administration to horses for doping control purposes.
Drug Test Anal, 14(2), 252-261.
https://doi.org/10.1002/dta.3174 Publication
Researcher Affiliations
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- Boehringer Ingelheim Vetmedica GmbH, Ingelheim am Rhein, Germany.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
- GIE-LCH, Laboratoire des Courses Hippiques, Verrières-le-Buisson, France.
MeSH Terms
- Animals
- Chromatography, Liquid / methods
- Horses
- Pilot Projects
- Pregnenediones / analysis
- Prodrugs
Grant Funding
- Boehringer Ingelheim
References
This article includes 39 references
- Baptist AP, Reddy RC. Inhaled corticosteroids for asthma: are they all the same?. J Clin Pharm Ther 2009;34(1):1-12.
- Mukker JK, Singh RSP, Derendorf H. Ciclesonide: A pro-soft drug approach for mitigation of side effects of inhaled corticosteroids. J Pharm Sci 2016;105(9):2509-2514.
- Lavoie J-P, Bullone M, Rodrigues N, Germim P, Albrecht B, von Salis-Soglio M. Effect of different doses of inhaled ciclesonide on lung function, clinical signs related to airflow limitation and serum cortisol levels in horses with experimentally induced mild to severe airway obstruction. Equine Vet J 2019;51(6):779-786.
- Pirie RS, Mueller H-W, Engel O, Albrecht B, von Salis-Soglio M. Inhaled ciclesonide is efficacious and well tolerated in the treatment of severe equine asthma in a large prospective European clinical trial. Equine Vet J 2021;53(6):1094-1104.
- Dietzel K, Engelstätter R, Keller A. Ciclesonide: an on-site-activated steroid. New Drugs for Asthma, Allergy and COPD 2001;31:91-93.
- Stoeck M, Riedel R, Hochhaus G. In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide. J Pharmacol Exp Ther 2004;309(1):249-258.
- Nave R, Wingertzahn MA, Brookman S, Kaida S, Matsunaga T. Safety, tolerability, and exposure of ciclesonide nasal spray in healthy and asymptomatic subjects with seasonal allergic rhinitis. J Clin Pharmacol 2006;46(4):461-467.
- Chopra D, Bhandari B, Wardhan N. Ciclesonide-a novel corticosteroid for the management of asthma. Curr Clin Pharmacol 2012;7(2):73-77.
- European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/referrals/alvesco
- Nave R, Bethke TD, van Marle SP, Zech K. Pharmacokinetics of [14C]ciclesonide after oral and intravenous administration to healthy subjects. Clin Pharmacokinet 2004;43(7):479-486.
- Nave R. Clinical pharmacokinetic and pharmacodynamic profile of inhaled ciclesonide. Clin Pharmacokinet 2009;48(4):243-252.
- Sato H, Nave R, Nonaka T, Mochizuki T, Takahama S, Kondo S. In vitro metabolism of ciclesonide in human nasal epithelial cells. Biopharm Drug Dispos 2007;28(1):43-50.
- Nave R, Fisher R, Zech K. In vitro metabolism of ciclesonide in human lung and liver precision-cut tissue slices. Biopharm Drug Dispos 2006;27(4):197-207.
- Nave R. Determination of lung deposition following inhalation of ciclesonide using different bioanalytical procedures. Bioanalysis 2010;2(4):807-814.
- Nonaka T, Nave R, McCracken N, Kawashimo A, Katsuura Y. Ciclesonide uptake and metabolism in human alveolar type II epithelial cells (A549). BMC Pharmacol 2007;7(1):12.
- Nave R, McCracken N. Metabolism of ciclesonide in the upper and lower airways: review of available data. J Asthma Allergy 2008;1:11-18.
- Sato H, Nave R, Nonaka T, Mochizuki T, Takahama S, Kondo S. In vitro activation of the corticosteroid ciclesonide in animal nasal mucosal homogenates. Biopharm Drug Dispos 2007;28(2):59-64.
- Sato H, Nave R, Nonaka T. Uptake and metabolism of ciclesonide and retention of desisobutyryl-ciclesonide for up to 24 hours in rabbit nasal mucosa. BMC Pharmacol 2007;7(1):7.
- Nave R, Meyer W, Fuhst R, Zech K. Formation of fatty acid conjugates of ciclesonide active metabolite in the rat lung after 4-week inhalation of ciclesonide. Pulm Pharmacol Ther 2005;18(6):390-396.
- Nave R, Gunawardena KA, Zech K, Bethke TD. Pharmacokinetic disposition of inhaled ciclesonide and its metabolite desisobutyryl-ciclesonide in healthy subjects and patients with asthma are similar. Int J Clin Pharmacol Ther 2006;44(01):1-7.
- Mutch E, Nave R, McCracken N, Zech K, Williams FM. The role of esterases in the metabolism of ciclesonide to desisobutyryl-ciclesonide in human tissue. Biochem Pharmacol 2007;73(10):1657-1664.
- Schaffner TJ, Skoner DP. Ciclesonide: a safe and effective inhaled corticosteroid for the treatment of asthma. J Asthma Allergy 2009;2:25-32.
- Peet CF, Enos T, Nave R, Zech K, Hall M. Identification of enzymes involved in phase I metabolism of ciclesonide by human liver microsomes. Eur J Drug Metab Pharmacokinet 2005;30(4):275-286.
- European Medicines Agency. CVMP assessment report for Aservo EquiHaler (EMEA/V/C/004991/0000). https://www.ema.europa.eu/en/documents/assessment-report/aservo-equihaler-epar-public-assessment-report_en.pdf
- Guo Z, Gu Z, Howell SR. Ciclesonide disposition and metabolism: pharmacokinetics, metabolism, and excretion in the mouse, rat, rabbit, and dog. Am J Ther 2006;13(6):490-501.
- Dalby R, Spallek M, Voshaar T. A review of the development of Respimat® Soft Mist™ Inhaler. Int J Pharm 2004;283(1-2):1-9.
- Pitcairn G, Reader S, Pavia D, Newman S. Deposition of corticosteroid aerosol in the human lung by Respimat® Soft Mist™ inhaler compared to deposition by metered dose inhaler or by Turbuhaler® dry powder inhaler. J Aerosol Med 2005;18(3):264-272.
- Weinbrenner A, Hüneke D, Zschiesche M. Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. J Clin Endocrinol Metab 2002;87(5):2160-2163.
- IFHA. International agreement on breeding, racing and wagering and appendixes. 2021, Article 6.
- Nave R, Watz H, Hoffmann H, Boss H, Magnussen H. Deposition and metabolism of inhaled ciclesonide in the human lung. Eur Respir J 2010;36(5):1113-1119.
- Fiet J, Le Bouc Y, Guéchot J. A liquid chromatography/tandem mass spectometry profile of 16 serum steroids, including 21-deoxycortisol and 21-deoxycorticosterone, for management of congenital adrenal hyperplasia. J Endocr Soc 2017;1(3):186-201.
- Owen LJ, Keevil BG. Supported liquid extraction as an alternative to solid phase extraction for LC-MS/MS aldosterone analysis?. Ann Clin Biochem 2013;50(5):489-491.
- AORC. AORC Guidelines for the Minimum Criteria for Identification by Chromatography and Mass Spectrometry. 2016.
- Ho ENM, Yiu KCH, Tang FPW. Detection of endogenous boldenone in the entire male horses. J Chromatogr B 2004;808(2):287-294.
- Guan F, Soma LR, Luo Y, Uboh CE, Peterman S. Collision-induced dissociation pathways of anabolic steroids by electrospray ionization tandem mass spectrometry. J am Soc Mass Spectrom 2006;17(4):477-489.
- Thevis M, Schänzer W. Mass spectrometry in sports drug testing: structure characterization and analytical assays. Mass Spectrom Rev 2007;26(1):79-107.
- Thevis M, Schänzer W. Mass spectrometric analysis of androstan-17β-ol-3-one and androstadiene-17β-ol-3-one isomers. J am Soc Mass Spectrom 2005;16(10):1660-1669.
- Garcia P, Paris A-C, Leufroy A, Popot M-A, Bonnaire Y. Quantitative analysis of a quaternary ammonium drug: ipratropium bromide by LC/ESI-MSn in horse plasma and urine. Biomed Chromatogr 2012;26(4):534-540.
- U.S. Food and Drug Administration. Freedom of information summary original new animal drug application - freedom of information summary original new animal drug application - NADA 141-533 Aservo® EquiHaler® Ciclesonide inhalation spray horses. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/8787
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