RT Journal Article
SR Electronic
T1 A Kinetic Evaluation of the Absorption, Efflux, and Metabolism of Verapamil in the Autoperfused Rat Jejunum
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 151
OP 158
DO 10.1124/jpet.102.045328
VO 305
IS 1
A1 Brendan M. Johnson
A1 Weiqing Chen
A1 Ronald T. Borchardt
A1 William N. Charman
A1 Christopher J. H. Porter
YR 2003
UL http://jpet.aspetjournals.org/content/305/1/151.abstract
AB P-glycoprotein (P-gp)-mediated drug efflux from the apical membrane of enterocytes is believed to modulate intestinal cytochrome P450 3A (CYP3A) metabolism by altering substrate access to the CYP3A enzyme. This interplay between P-gp and CYP3A was investigated in a rat in situ model of intestinal permeation, where a recirculating luminal perfusion of the jejunum was coupled with mesenteric vein blood collection to simultaneously monitor the uptake, transport, and metabolism of the P-gp and CYP3A substrate, verapamil. Transport of intact verapamil into the venous blood was increased by 160, 84, and 160%, and the intestinal extraction ratio on passage across the jejunum was reduced by 15, 24, and 97% by inhibitors of P-gp [PSC833 ([3′-keto-Me-Bmt1]-[Val2]-cyclosporin)], CYP3A (midazolam), or P-gp and CYP3A (ketoconazole), respectively, when present in the luminal perfusate and compared with control experiments. Compartmental kinetic analysis of the data revealed that inhibition of P-gp did not affect the rate constant describing verapamil metabolism but, rather, increased the intestinal uptake of verapamil and stimulated a disproportionate increase in verapamil transport into the venous blood. The increase in verapamil transport, in the absence of changes to metabolism, reduced the intestinal extraction ratio. This finding may be explained by saturation of intracellular verapamil binding sites within the intestinal tissue in response to increased verapamil uptake resulting from P-gp inhibition. The current findings confirm previous in vitro and theoretical approaches which suggest that P-gp can modulate the extent of intestinal extraction of P-gp/CYP3A substrates. The American Society for Pharmacology and Experimental Therapeutics