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Vol. 296, Issue 2, 584-591, February 2001
Sections of Gastrointestinal Science (R.H.S., C.A.O., A.W., G.W.)
and Injury Research (G.L.C.), Clinical Division I, University of
Manchester, Hope Hospital, Salford, United Kingdom; and School of
Pharmacy and Pharmaceutical Science, University of Manchester,
Manchester, United Kingdom (M.R.)
Intestinal drug efflux mediated by P-glycoprotein and other ABC
transporters is widely accepted as a reason for low or variable oral
absorption. However, little is known about species and regional differences in P-glycoprotein so the functional and predictive relevance of observations made in cell models 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
functional role of other ABC transporters in the transport of these
compounds was 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
µM), increasing in rat from small to large intestine. In contrast,
maximal transporter activity varied over a 4- to 5-fold range with
ileum > jejunum > colon. Similar regional differences in
efflux were also observed with vinblastine. Maximal efflux levels were
similar in Caco-2 and ileum for both substrates, suggesting that Caco-2
may quantitatively predict small intestinal drug efflux. Digoxin efflux
kinetics was virtually identical in rat and human colon. Inhibitor
studies showed that digoxin and vinblastine efflux in intestinal
tissues was mediated by P-glycoprotein, although a minor component
could be attributed to multidrug resistance-related protein
(MRP)-like transporters in Caco-2. This 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 gathered from in vitro systems.
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