Universität zu Köln

Thevis, Mario, Geyer, Hans, Thomas, Andreas ORCID: 0000-0003-1199-0743, Tretzel, Laura, Bailloux, Isabelle, Buisson, Corinne, Lasne, Francoise, Schaefer, Maximilian S., Kienbaum, Peter ORCID: 0000-0002-0655-9177, Mueller-Stoever, Irmela and Schaenzer, Wilhelm (2015). Formation of the diuretic chlorazanil from the antimalarial drug proguanil-Implications for sports drug testing. J. Pharm. Biomed. Anal., 115. S. 208 - 214. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1873-264X

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Abstract

Chlorazanil (Ordipan, N-(4-chloropheny1)-1,3,5-triazine-2,4-diamine) is a diuretic agent and as such prohibited in sport according to the regulations of the World Anti-Doping Agency (WADA). Despite its introduction into clinical practice in the late 1950s, the worldwide very first two adverse analytical findings were registered only in 2014, being motive for an in-depth investigation of these cases. Both individuals denied the intake of the drug; however, the athletes did declare the use of the antimalarial prophylactic agent proguanil due to temporary residences in African countries. A structural similarity between chlorazanil and proguanil is given but no direct metabolic relation has been reported in the scientific literature. Moreover, chlorazanil has not been confirmed as a drug impurity of proguanil. Proguanil however is metabolized in humans to N-(4-chloropheny1)-biguanide, which represents a chemical precursor in the synthesis of chlorazanil. In the presence of formic acid, formaldehyde, or formic acid esters, N-(4-chloropheny1)-biguanide converts to chlorazanil. In order to probe for potential sources of the chlorazanil detected in the doping control samples, drug formulations containing proguanil and urine samples of individuals using proguanil as antimalarial drug were subjected to liquid chromatography-high resolution/high accuracy mass spectrometry. In addition, in vitro simulations with 4-chlorophenyl-biguanide and respective reactants were conducted in urine and resulting specimens analyzed for the presence of chlorazanil. While no chlorazanil was found in drug formulations, the urine samples of 2 out of 4 proguanil users returned findings for chlorazanil at low ng/mL levels, similar to the adverse analytical findings in the doping control samples. Further, in the presence of formaldehyde, formic acid and related esters, 4-chlorophenyl-biguanide was found to produce chlorazanil in human urine, suggesting that the detection of the obsolete diuretic agent was indeed the result of artefact formation and not of the illicit use of a prohibited substance. (C) 2015 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Thevis, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Geyer, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Andreas UNSPECIFIED orcid.org/0000-0003-1199-0743 UNSPECIFIED Tretzel, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Bailloux, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Buisson, Corinne UNSPECIFIED UNSPECIFIED UNSPECIFIED Lasne, Francoise UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaefer, Maximilian S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kienbaum, Peter UNSPECIFIED orcid.org/0000-0002-0655-9177 UNSPECIFIED Mueller-Stoever, Irmela UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaenzer, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-387130
DOI:	10.1016/j.jpba.2015.07.017
Journal or Publication Title:	J. Pharm. Biomed. Anal.
Volume:	115
Page Range:	S. 208 - 214
Date:	2015
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1873-264X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PERFORMANCE LIQUID-CHROMATOGRAPHY; MASS-SPECTROMETRY; BIOLOGICAL-FLUIDS; URINE; METABOLITES; FORMALDEHYDE; PHARMACOKINETICS; CHLOROQUINE; HEADSPACE; ORPIDAN Multiple languages Chemistry, Analytical; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38713