DIETARY SALT INCREASES FIRST-PASS ELIMINATION OF ORAL QUINIDINE

Background: Some cytochrome P450 (CYP) enzymes, including CYP3A, are e xpressed not only in the liver but also in the intestine; the latter m ay therefore be an important site of drug disposition. Animal data sug gests that dietary salt modulates expression of renal CYPs. We therefo re hypothesized that intestinal CYP3A may be similarly modulated by di etary salt. Methods: The effect of changes in dietary salt on the disp osition of two CYP3A substrates, quinidine (administered orally and in travenously) and C-14-erythromycin (administered intravenously) were d etermined after normal volunteers were given high-salt (400 mEq/day) a nd low-salt (10 mEq/day) diets for 7 to 10 days each. Results: Plasma concentrations after oral quinidine were significantly lower during th e high-salt phase, with the difference between the two treatments attr ibutable to changes within the first 1 to 4 hours after administration , For example, the area under the plasma concentration-time curve for the first hour after drug administration was 0.56 +/- 0.38 mu g . hr/m l for the high-salt diet compared with 1.57 +/- 0.60 mu g . hr/ml for the low-salt diet (p < 0.05). Similarly, the peak plasma concentration (C-max) achieved was lower and the time to reach C-max was later for the high-salt diet (p < 0.05). In contrast, the terminal phase elimina tion half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug. The erythromycin bre ath test was unaffected by the dietary treatments. Conclusions: These results indicate an effect of dietary salt on the presystemic disposit ion of orally administered quinidine. Although the mechanism(s) of CYP 3A activity modulation is unknown, this finding may be important in de termining drug availability in conditions associated with abnormal sal t homeostasis.