Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia

Intestinal drug efflux mediated by P-glycoprotein and other ABC transporter s is widely accepted as a reason for low or variable oral absorption. Howev er, little is known about species and regional differences in P-glycoprotei n so the functional and predictive relevance of observations made in cell m odels such as Caco-2 is uncertain. The aim of this study was to define the kinetics of drug efflux in rat and human intestinal tissues in vitro using the "reference" substrates digoxin and vinblastine. The expression and func tional role of other ABC transporters in the transport of these compounds w as also investigated. Saturable, verapamil-sensitive efflux of digoxin was observed in all intestinal regions. Apparent affinity of the efflux process varied within a relatively narrow range (50-92 muM), increasing in rat fro m small to large intestine. In contrast, maximal transporter activity varie d over a 4- to 5-fold range with ileum. jejunum. colon. Similar regional di fferences in efflux were also observed with vinblastine. Maximal efflux lev els were similar in Caco-2 and ileum for both substrates, suggesting that C aco-2 may quantitatively predict small intestinal drug efflux. Digoxin effl ux kinetics was virtually identical in rat and human colon. Inhibitor studi es showed that digoxin and vinblastine efflux in intestinal tissues was med iated by P-glycoprotein, although a minor component could be attributed to multidrug resistance-related protein (MRP)-like transporters in Caco-2. Thi s study has analyzed the differential functional expression of drug efflux along the gastrointestinal tract. Such data will be critical in developing predictive models of P-glycoprotein-mediated efflux using information gathe red from in vitro systems.