Darbar D, Dell'Orto S, Mörike K, Wilkinson G R, Roden D M
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Clin Pharmacol Ther. 1997 Mar;61(3):292-300. doi: 10.1016/S0009-9236(97)90161-2.
Some cytochrome P450 (CYP) enzymes, including CYP3A, are expressed not only in the liver but also in the intestine; the latter may therefore be an important site of drug disposition. Animal data suggests that dietary salt modulates expression of renal CYPs. We therefore hypothesized that intestinal CYP3A may be similarly modulated by dietary salt.
The effect of changes in dietary salt on the disposition of two CYP3A substrates, quinidine (administered orally and intravenously) and 14C-erythromycin (administered intravenously) were determined after normal volunteers were given high-salt (400 mEq/day) and low-salt (10 mEq/day) diets for 7 to 10 days each.
Plasma concentrations after oral quinidine were significantly lower during the high-salt phase, with the difference between the two treatments attributable 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 microgram.hr/ml for the high-salt diet compared with 1.57 +/- 0.60 micrograms.hr/ml for the low-salt diet (p < 0.05). Similarly, the peak plasma concentration (Cmax) achieved was lower and the time to reach Cmax was later for the high-salt diet (p < 0.05). In contrast, the terminal phase elimination half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug. The erythromycin breath test was unaffected by the dietary treatments.
These results indicate an effect of dietary salt on the presystemic disposition of orally administered quinidine. Although the mechanism(s) of CYP3A activity modulation is unknown, this finding may be important in determining drug availability in conditions associated with abnormal salt homeostasis.
一些细胞色素P450（CYP）酶，包括CYP3A，不仅在肝脏中表达，也在肠道中表达；因此，肠道可能是药物处置的重要部位。动物数据表明，饮食中的盐会调节肾脏CYP的表达。因此，我们推测肠道CYP3A可能同样受到饮食中盐的调节。
在正常志愿者分别接受高盐（400 mEq/天）和低盐（10 mEq/天）饮食7至10天后，测定饮食中盐的变化对两种CYP3A底物（口服和静脉注射奎尼丁以及静脉注射14C-红霉素）处置的影响。
高盐阶段口服奎尼丁后的血浆浓度显著降低，两种治疗之间的差异归因于给药后1至4小时内的变化。例如，给药后第一小时血浆浓度-时间曲线下面积，高盐饮食组为0.56±0.38微克·小时/毫升，低盐饮食组为1.57±0.60微克·小时/毫升（p<0.05）。同样，高盐饮食组达到的血浆峰值浓度（Cmax）较低，达到Cmax的时间较晚（p<0.05）。相比之下，两种饮食的终末相消除半衰期相似，静脉给药时未发现处置差异。红霉素呼气试验不受饮食治疗的影响。
这些结果表明饮食中的盐对口服奎尼丁的首过处置有影响。尽管CYP3A活性调节的机制尚不清楚，但这一发现对于确定与盐稳态异常相关情况下的药物可利用性可能很重要。
