Intestinal drug efflux: formulation and food effects

The intestine, primarily regarded as an absorptive organ, is also prepared for the elimination of certain organic acids, bases and neutral compounds d epending on their affinity to intestinal carrier systems. Several of the tr ansport systems known to mediate efflux in the major clearing organs - live r and kidney - are also expressed in the intestine. Examples of secretory t ransporters in the intestine are P-glycoprotein, members of the multidrug r esistance associated protein family, breast cancer resistance protein, orga nic cation transporters and members of the organic anion polypeptide family . In this communication, the P-glycoprotein mediated intestinal secretion o f talinolol, a model compound showing metabolic stability, has been investi gated in the jejunum, ileum and colon of rat intestine by single-pass perfu sion. A model has been developed which demonstrates an increase in carrier- mediated secretion in the order jejunum < ileum < colon. Furthermore, the p otency of common excipients in peroral drug products towards inhibition of P-gp mediated secretion has been investigated using a radioligand-binding a ssay and transport studies in Caco-2 cell monolayers. Finally, evidence is provided which demonstrates that constituents of grapefruit juice not only may influence intestinal drug metabolism, but can also interfere with secre tory transport systems, leading to a new and yet undescribed mechanism in d rug-food interactions. (C) 2001 Elsevier Science BY. All rights reserved.