CHARACTERIZATION OF HYDROXYLATED METABOLITES OF PROPAFENONE IN HEALTHY CHINESE VOLUNTEERS

AIM: To investigate the racial differences of propafenone metabolism, the hydroxylated metabolites of propafenone were identified in Chinese volunteers. METHODS: Urine samples were collected and extracted by liquid liquid method after a single oral administration of 300 mg propafenone hydrochloride to ten healthy Chinese volunteers. The hydroxylated metabolites in urine were detected by ion trap LC/MS using a combination of selected ion monitoring ( m/z 358±1 5), and multi stage full scan techniques. RESULTS: Two hydroxylated propafenone derivatives in were found 0～12 h urine. Based on MS data, structures of the two metabolites were postulated as 5-hydroxypropafenone and 4′-hydroxypropafenone, respectively. The structure of 5-hydroxypropafenone was confirmed by comparing the LC/MS retention time and mass spectral data with authentic substance. The reference substance of 4′-hydroxypropafenone was prepared by microbial transformation method combined with semi preparative HPLC, and the structure was elucidated via MS and NMR spectrometry. In ten Chinese volunteers, both 4′-and 5-hydroxy isomers were detected, and their mean ratio of amount in 12 h urine was about 1∶5 based on LC/MS analysis, whereas only 5-hydroxypropafenone had been reported in Caucasian volunteers. In addition, the enantiomers of two hydroxylated metabolites in Chinese volunteers were separated by Chiral AGP column. The results demonstrated that no significant stereoselectivity in the oxidative metabolism of PPF enantiomers to 4′-and 5-hydroxypropafenone was found after administration of racemic PPF to healthy volunteers. CONCLUSION: Compared with the metabolic results obtained from Caucasian volunteers, Chinese volunteers may have a broader spectrum of metabolites with respect to the hydroxylation capacity.