Modulation by dietary salt of verapamil disposition in humans

Background-The intestine is an increasingly well-recognized site of first-p ass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes ex tensive first-pass metabolism. Methods and Results-Eight normal volunteers received 120 mg of racemic vera pamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterat ed verapamil with the morning oral dose on days 7, 14, and 21. Each study d ay was preceded by 7 days on a fixed-salt diet: in 5 subjects, the initial study was conducted during a low-salt (10 mEq/d) diet, the second study dur ing a high-salt (400 mEq/d)diet, and the third during a low-salt diet, wher eas in the other 3 subjects, the sequence of diets was reversed. Plasma con centrations of both unlabeled enantiomers (ie, from oral therapy) were sign ificantly (P<0.05) lower during the high-salt phase (eg, mean area under th e time-concentration curve [0 to 12 hours] for S-verapamil: 7765+/-2591 ng . min . mL(-1) [high salt] versus 12514+/-3527 ng . min . mL(-1) [low salt] , P<0.05). Peak plasma concentrations were significantly lower and the exte nt of PR interval prolongation significantly blunted with the high-salt die t. In contrast, data with labeled drug (je, reflecting the intravenous rout e) were nearly identical for the 2 diets, Conclusions-These data indicate that a clinically important component of pr esystemic drug disposition occurs at the prehepatic (presumably intestinal) level and is sensitive to dietary salt.