The effect of dietary salt on verapamil disposition in relation to MDR1 C3435T / G2677T genotype

Abstract

Although the effect of MDR1 genotype on oral bioavailability of verapamil are remained controversial, dietary salt might affect on its disposition in relation to MDR1 genetic polymorphism. To evaluate the influences of dietary salt on the enantioselective disposition of verapamil in relation to MDR1 genotype, ten healthy male subjects(5 with 3435CC/2677GG and others with 3435TT/2677TT) were enrolled in randomized crossover study. Five were served low salt diet (~1.5g/day) and others did high salt diet (25g/day) for 7 days. After a week-washout, the salt diet sequence was switched. On day 7, 14, and 21, blood and urine samples were serially collected upto 24 hours after oral dosing of 240mg verapamil. The concentration of verapamil enantiomers and its metabolites were determined using LC/MS/MS. The plasma concentrations of both enantiomers and R/S AUCinf ratios were not significantly different between trials of each diet in both genotype group. Cmax, AUC0–4hr, and AUCo-∞ of verapamil in subjects with 3435TT/2677TT were higher than in those with 3435CC/2677GG in both trial, but the difference was not statistically significant. The R/S AUCinf ratio was not also significantly different between MDR1 genotype groups. These results did not demonstrate that the dietary salt affects on the disposition of verapamil. However, this study indicated that subject with MDR1 3435T/2677T variant might show the higher oral bioavailability of verapamil than those with MDR1 3435C/2677G due to low P-glycoprotein activity. Clinical Pharmacology & Therapeutics (2005) 77, P87–P87; doi: 10.1016/j.clpt.2004.12.226