Drug monitoring and pharmacokinetics

Clenbuterol [4-amino-c~ [(tert.-butylamino)methyl]-3.5-dichlorobenzylalcohol] is a very potent #-2-mimetic drug, which differs from the other drugs of this class in its long half-life of about 30 h. Until now, only metabolic pattern have been published [1, 2]. There is no detailed information about the structure of metabolites. We isolated the metabolites of dog urine with HPLC-techniques and compared the metabolic pattern with those of man, rabbit and rat. 98% of the metabolites in urine (= 88% of administered dose!) were elucidated by NMR, MS, FAB-MS, derivatisation and comparison with reference material. As all positions of metabolic attack for enzymes which are able to metabolize catechol-structures are blocked in Clenbuterol, its biotransformation is rather different to catechols. The main excretion products in dog urine are (Fig. 1) parent compound (24%), degradation products of the aliphatic side chain: 4-Amino-3,5-dichloro-mandelic-acid (20%), the corresponding benzoic acid (9%), the corresponding hippuric acid (19%). There are four conjugation products of the parent compound: N-Sulfamate (5%), Oand N-Gtucuronides (5%) and an interestingly O-ethylation (2%) of the alcohol function. We further found indications of the C-C cleavage between the aromatic moiety and the aliphatic side chain yielding a phenol and the aliphatic aminoacid t-butylglycine (2%). The metabolic patterns in dog, man, rat, rabbit are qualitatively rather similar in these species. However, there are quantitative differences, e.g. the amount of unchanged drug is highest in man 61%, 37% in rabbit, 26% in rat and 24% in dog.