Objective: To screen for inhibitory effects of diosmin on cytochrome P(450)-mediated metabolism of metronidazole in healthy volunteers.
Design: Before/after non-blinded investigation conducted in healthy male volunteers.
Methods: After an overnight fast, metronidazole (two 400-mg tablets) was administered to 12 volunteers, either alone or after a 9-day pretreatment period with a once-daily dose of diosmin 500-mg tablets under direct observation. Serum concentrations of metronidazole up to 48 h postdose and urinary concentrations of metronidazole and its two major metabolites up to 24 h postdose were measured using reversed-phase high-performance liquid chromatography.
Results: Metronicazole plasma AUC((0- infinity )) and C(max) were significantly higher after diosmin pretreatment by (mean) 27% and 24%, respectively. However, time to reach peak concentration (t(max)) was not affected significantly. Urinary excretion of acid and hydroxy metabolites in urine was decreased significantly, while excretion of unchanged metronidazole was increased.
Conclusion: Diosmin pretreatment significantly altered the metabolism of metronidazole, as demonstrated by changes in plasma pharmacokinetics as well as by urinary recovery of both parent drug and its major metabolites. This may be caused by the inhibition of cytochrome P(450) enzymes.