Correlation between the systemic clearance of drugs and their food effects in humans.

摘要

CONTEXT: Food effects were defined as positive, when coadministration of food causes an increase in the extent of absorption (AUC(0-infinity)) of a drug when compared with fasted state drug administration and no effect when coadministration of food causes no change in AUC(0-infinity). In general, low solubility drugs exhibit positive food effects due to improved solubility in fed state administration. But, certain high-solubility and high-permeability drugs that undergo extensive presystemic metabolism exhibit positive food effects because of the increased splanchnic hepatic blood flow in the fed state presumably causing a fraction of drug to bypass first-pass metabolism during absorption. OBJECTIVE: In this study, systemic clearance (Cl) of structurally diverse high-permeability and high-solubility drugs was correlated to their food effects to explore whether drugs undergoing low clearance exhibited no food effects and drugs undergoing high clearance exhibited positive food effects. METHODS: Six drugs exhibiting positive food effects and nine drugs exhibiting no food effects (for comparison) were selected for linear regression analysis. RESULTS: Regression analysis of the selected drugs indicated that percent food effects correlated linearly to Cl and fitted the equation: percent food effects = 0.9163 x Cl - 6.4789. The R(2), p-value and power of the regression model were >0.88, 0.9999, respectively indicating the direct correlation between Cl and food effects of the selected model drugs; other statistical tests validated the model. CONCLUSION: The model indicated that high-solubility and high-permeability drugs undergoing Cl of more than 27 L/h may exhibit statistically significant positive food effects.