Modulation of effect of dietary salt on prehepatic first-pass metabolism: effects of beta-blockade and intravenous salt loading.
We previously demonstrated that increased dietary salt markedly decreases plasma quinidine concentrations shortly after p.o. dosing, without an effect on the drug's terminal elimination half-life or concentrations after i.v. administration. These findings suggest an effect of dietary salt on intestinal metabolism or transport of the drug. Because one effect of salt loading is sympathetic inhibition, we examined the effect of beta-adrenoceptor blockade on salt-related changes in quinidine disposition. Furthermore, we examined whether the action of salt is local or systemic by determining the effect of salt loading by the i.v. route. To assess the effect of beta-blockade, quinidine disposition was studied in eight normal volunteers after a single p.o. dose of quinidine; data were obtained after 1 week on a high-salt diet (400 mEq/day) and 1 week on a low-salt diet (10 mEq/day) during chronic nadolol and compared with those previously obtained in the same subjects without the beta-blocker. beta-Blockade had no effect on oral clearance during the high-salt diet [0.28 +/- 0.1 (quinidine + nadolol) versus 0.30 +/- 0.2 liters/h/kg (quinidine alone)] but increased clearance on the low-salt diet from 0.23 +/- 0.1 to 0.29 +/- 0.1 liters/h/kg (p <. 05). For the i.v. salt study, the disposition of single p.o. and single i.v. doses of quinidine was determined on two occasions in eight subjects: once during a low-salt diet (10 mEq/day) and once during the same diet, supplemented by 400 mEq/day NaCl i.v. for 8 days. In contrast to our findings after p.o. salt loading, i.v. salt loading did not alter the pharmacokinetics of p.o. quinidine. Taken together, these data implicate a local alteration of drug-metabolizing activity and/or drug transport in the intestinal mucosa as the major effect of dietary salt on the disposition of p.o. quinidine and further suggest that beta-adrenergic activation by a low-salt diet is one component of a signaling pathway whereby intestinal drug disposition is suppressed, resulting in increased oral bioavailability.
Fromm
M F
MF
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Darbar
D
D
Dell'Orto
S
S
Roden
D M
DM
D000284:Administration, Oral; D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D004039:Diet, Sodium-Restricted; D005080:Exercise Test; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009248:Nadolol / Q000494:pharmacology; D011802:Quinidine / Q000008:administration & dosage / Q000493:pharmacokinetics; D012964:Sodium / Q000008:administration & dosage / Q000494:pharmacology; D012982:Sodium, Dietary / Q000008:administration & dosage / Q000494:pharmacology*; D014018:Tissue Distribution
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D012982:Sodium, Dietary; D009248:Nadolol; D012964:Sodium; D011802:Quinidine