PT  - JOURNAL ARTICLE
AU  - Brendan M. Johnson
AU  - Weiqing Chen
AU  - Ronald T. Borchardt
AU  - William N. Charman
AU  - Christopher J. H. Porter
TI  - A Kinetic Evaluation of the Absorption, Efflux, and Metabolism of Verapamil in the Autoperfused Rat Jejunum
AID  - 10.1124/jpet.102.045328
DP  - 2003 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 151--158
VI  - 305
IP  - 1
4099  - http://jpet.aspetjournals.org/content/305/1/151.short
4100  - http://jpet.aspetjournals.org/content/305/1/151.full
SO  - J Pharmacol Exp Ther2003 Apr 01; 305
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