THE CHARACTERIZATION OF THE METABOLITES OF RANOLAZINE IN MAN BY LIQUID-CHROMATOGRAPHY MASS-SPECTROMETRY

The metabolism of ranolazine (RS-43285) or -hydroxy-3-(2-methoxyphenox y)-propyl]-1-piperazine acetamide dihydrochloride was investigated in man using plasma samples obtained from four different clinical studies . The metabolite profiles following single and multiple doses of 342 m g instant release (IR) ranolazine, following multiple doses of 1000 mg sustained release (SR) ranolazine and following dosing with both rano lazine (IR) and a potentially co-administered drug, diltiazem, were co mpared. Metabolism of ranolazine in man was shown by LC/MS analysis to be extensive with up to seven primary routes of metabolism identified . N-dealkylation by hydrolysis at the piperazine ring produced three m etabolites whilst O-demethylation and O-dearylation at the methoxyphen oxy moiety produced a further two compounds. Additionally, hydrolysis of the amide group formed one other species. Oxygenation at various po ints in the molecule produced a further four metabolites. Direct conju gation of ranolazine with glucuronic acid and with an uncharacterized adduct were also identified as a route of elimination. Ten other biotr ansformation products were formed as a result of multiple metabolic st eps. Conjugation was also associated with the desmethyl metabolite (gl ucuronide and unidentified conjugates) of hydroxylated ranolazine. In a previous publication (Journal of Chromatography, 1995, accepted for publication) semi-quantitative analyses of pooled plasma from the stud y where ranolazine was dosed at 1000 mg twice daily showed that of the twelve metabolites studied only four accounted for AUC's in excess of 10% of the ranolazine AUC.