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The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan.

ABSTRACT: A low sodium diet enhances the hemodynamic effect of renin-angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1-week washout for diet. Eligible subjects were fed with either low sodium (50 mEq/day) diet or high sodium diet (300 mEq/day) for 7 days in the first hospitalization period and the other diet in the second period. On the seventh morning of each period, subjects received a single dose of fimasartan 60 mg in a fasted state. The serial plasma concentrations of fimasartan, serum aldosterone concentration (SAC), and plasma renin activity (PRA) were measured for pharmacokinetic-pharmacodynamic analysis. Sixteen subjects completed the study satisfying the compliance test for diets. Although the mean systemic exposure of fimasartan is slightly (?10%) decreased on a high sodium diet, the difference was not statistically or clinically significant (P>0.05). The SAC and PRA after fimasartan administration were highly dependent on their baseline levels. The dietary sodium content influenced the baseline of SAC and PRA, but did not influence the ratio change of SAC and PRA after fimasartan treatment. The ratio change of SAC after fimasartan treatment was correlated to the systemic exposure of fimasartan (P<0.05), while the correlation between the ratio change of PRA after fimasartan treatment and the individual systemic exposure of fimasartan was not significant (P>0.05). In conclusion, the pharmacokinetics of fimasartan and ratio changes of SAC and PRA after fimasartan treatment were not significantly influenced by dietary sodium content.

SUBMITTER: Gu N

PROVIDER: S-EPMC4844258 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan.

Gu Namyi N Cho Joo-Youn JY Shin Kwang-Hee KH Jang In-Jin IJ Rhee Moo-Yong MY

Drug design, development and therapy 20160419

A low sodium diet enhances the hemodynamic effect of renin-angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1- ...[more]

PMID: 27143858

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Project description:BackgroundConcomitant drug administration is a general phenomenon in patients with chronic diseases such as diabetes mellitus. Among the currently available oral antidiabetic drugs, gliclazide is a commonly prescribed drug considering its multiple benefits in diabetic patients. Aprepitant is a commonly prescribed antiemetic drug which is mainly metabolized by CYP3A4, reported to have modest inductive and inhibitory effects on CYP2C9 and CYP3A4, respectively. Since gliclazide is metabolized by CYP2C9 (major) and CYP3A4 (minor), it is very difficult to predict the influence of aprepitant and its metabolic interaction with gliclazide. Considering the complexity associated with the combination of aprepitant and gliclazide, this study was designed to evaluate the influence of aprepitant on the pharmacodynamics (PD) and pharmacokinetics (PK) of gliclazide in animal models.MethodsThe PD interaction studies were conducted in both rodent (normal and alloxan-induced diabetic rats) and non-rodent (rabbits) animal models (n = 6) while the PK interaction study was conducted in normal rabbits (n = 6). An extrapolated human therapeutic oral dose of gliclazide, aprepitant and their combination were administered to rats and rabbits with 7 days washout between each treatment. For the multiple-dose interaction study, the same groups were administered with an interacting drug (aprepitant) for 7 days and then the combination of aprepitant and gliclazide on the 8th day. From the collected animal blood samples, blood glucose (by Glucose-Oxidase/Peroxidase method), insulin (by ELISA method) and gliclazide concentration levels (by HPLC method) were determined. Non-compartmental PK analysis was conducted by Phoenix WinNonlin software to determine the PK parameters of gliclazide. Statistical analysis was performed by student's paired t-test.ResultsThe pharmacodynamic activity (blood glucose reduction and insulin levels) of gliclazide was significantly (p < 0.05) influenced by aprepitant in normal and diabetic condition without any convulsions in animals. There was a significant (p < 0.05) increase in concentration levels and Area Under the Curve of gliclazide while significant (p < 0.05) decrease in clearance levels of gliclazide in rabbits. The PK interaction with gliclazide is relatively more with the multiple dose treatment of aprepitant over single dose treatment.ConclusionIn combination, aprepitant significantly influenced the pharmacodynamic activity of gliclazide in animal models. Considering this, care should be taken when this combination is prescribed for the clinical benefit in diabetic patients.

Dataset Information

The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan.

Publications

The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan.

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