Identification of the metabolites of roxithromycin in humans

The semisynthetic antibiotic roxithromycin (RXM) exists in an (E)-configura tion. Metabolites of RXM in the bile of four cholecystectomy patients with T-tube drainage and in the urine and plasma of four healthy volunteers afte r single oral doses of 150 mg of RXM were investigated. A total of 15 metab olites were found in bile, urine, and plasma by HPLC with ion trap mass spe ctrometric and electrochemical detection. These metabolites were identified as descladinose derivative of RXM (M1), erythromycin-oxime (M2), N-, O-, a nd N,O-di-demethylated derivatives of RXM (M3, M4, and M6), and N-mono- and N-di-demethylated derivatives of erythromycinoxime (M5 and M7), as well as the (Z)-isomers (M8-M15) of RXM and metabolites M1 to M7, respectively. St ructures of six major metabolites (M1-M4, M8, and M10) were established by chromatographic and mass spectrometric determination and comparison with sy nthesized standards. The stability of RXM and the six synthesized substance s was investigated to exclude artifact products. These results, together wi th previous findings, suggest that biotransformation pathways elucidated fo r RXM include: 1) isomerization of RXM derivatives, from E-isomer to Z-isom er; 2) O-demethylation; 3) N-demethylation; 4) hydrolysis of the cladinose moiety; and 5) dealkylation of the oxime ether side chain. Secondary metabo lism via these pathways was also evidenced. The O-demethylation and isomeri zation of RXM derivatives represent two novel biotransformation pathways re covered for RXM.