Modulation by Dietary Salt of Verapamil Disposition in Humans

Abstract

Background-The intestine is an increasingly well-recognized site of first-pass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes extensive first-pass metabolism. Methods and Results-Eight normal volunteers received 120 mg of racemic verapamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterated verapamil with the morning oral dose on days 7, 14, and 21. Each study day 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 during a high-salt (400 mEq/d) diet, and the third during a low-salt diet, whereas in the other 3 subjects, the sequence of diets was reversed.

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

“…This conclusion is supported by the lower levels of atenolol recovery in urine during SR. These results are consistent with previous findings showing that a high-sodium diet results in lower plasma concentrations of orally administered verapamil 6 and quinidine 5,7 than a low-sodium diet. This study extends these findings to some of the drugs interfering directly with the RAS, for which the interaction with dietary sodium intake is critical and provides new insight in the putative mechanisms involved in dietary salt-dependent changes in drug absorption.…”

“…A high-sodium diet decreases the plasma concentration of oral quinidine by ≈20% 5,7 and that of oral verapamil by ≈60%. 6 Interestingly, in 2 separate experiments, we had already observed a similar phenomenon with the direct renin inhibitor aliskiren, 11,12 which is also a Pg-P substrate. 26 The precise mechanism responsible for the pharmacokinetic interaction with dietary sodium remains hypothetical and is probably multifactorial, including salt-induced changes to sympathetic gut function 7 or changes to the activity or expression of drug transporters (eg, Pg-P) or CYP3A4 in the intestinal mucosa.…”

“…The pharmacodynamic consequences of dietary sodium-induced changes in the pharmacokinetics of these drugs were assessed by determining the druginduced increase in plasma renin concentration (PRC) for the angiotensin-converting enzyme inhibitor and the angiotensin II receptor blockers resulting from interruption of the angiotensin II negative feedback loop on renin release 10 ; and the drug-induced changes in PR interval duration and heart rate (HR) on ECG recordings for atenolol. 6 We found that sodium status modulated the pharmacokinetics of candesartan and atenolol, with measurable but mild effects on the selected pharmacodynamic end points.…”

“…[23][24][25] The absorption of candesartan cilexetil is enhanced by Pg-P inhibitors, such as cyclosporine A and verapamil. 23 We suggest that the main mechanism involved in the decrease in candesartan bioavailability with SR may be the modulation of Pg-P activity or expression by SR/SD state, as suggested for verapamil and quinidine, [5][6][7] which are both Pg-P and cytochrome P 3A4 (CYP3A4) substrates. A high-sodium diet decreases the plasma concentration of oral quinidine by ≈20% 5,7 and that of oral verapamil by ≈60%.…”

“…[1][2][3][4] A pharmacokinetic interaction with the sodium content of the diet has been reported for drugs that do not interfere with the RAS. [5][6][7] We therefore compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of various RAS blockers administered to normotensive healthy male subjects: an angiotensin-converting enzyme inhibitor (ramipril) and 2 different angiotensin II receptor blockers (candesartan cilexetil and valsartan). We selected 2 different angiotensin II receptor blockers to investigate whether in a same class, drugs with different physicochemical properties and pharmacokinetic profiles could be affected differently by the sodium content of the diet.…”