EVIDENCE FOR A NEW AND MAJOR METABOLIC PATHWAY OF CLENBUTEROL INVOLVING IN-VIVO FORMATION OF AN N-HYDROXYARYLAMINE

Clenbuterol is a beta-adrenergic agonist widely but illegally used in cattle as a growth promoter. The metabolic fate of this drug remains u nknown in the main target species, i.e. the bovine, and only limited d ata have been published concerning its biotransformations in laborator y animals. A metabolic study has been carried out in the rat using H-3 - and C-14-labeled clenbuterol. Urine appeared to be the major excreti on pathway. Using a soft technique for urine preparation, extraction, and purification, as well as adequate analytical tools in order to pre serve labile metabolites, N-oxidation products of the parental drug on the primary amine function were identified for the first time. Clenbu terol hydroxylamine was the major compound, but 4-nitroclenbuterol was also detected. The metabolic pathway leading to the formation of clen buterol hydroxylamine prevails at high dosages. Clenbuterol hydroxylam ine (but not 4-nitroclenbuterol) was also formed extensively when the drug was incubated with rat liver microsomal fractions in aerobic cond itions. It is concluded that oxide reduction reactions during urine pr eparation have previously impaired the identification of this toxicolo gically important clenbuterol metabolic route.