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Vol. 286, Issue 3, 1166-1170, September 1998

Transport of L-Valine-Acyclovir Via the Oligopeptide Transporter In The Human Intestinal Cell Line, Caco-2

Remco L. A. de Vrueh1, Philip L. Smith and Chao-Pin Lee

Department of Drug Delivery, Pharmaceutical Technologies, Smithkline Beecham Pharmaceuticals, Collegeville, Pennsylvania

It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to L-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the D-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of L-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium. Only the mucosal-to-serosal transport of acyclovir was increased by conjugation with L-valine (~7-fold), suggesting the involvement of a carrier-mediated mechanism. This conclusion was supported by the finding that this increase was saturable. The mucosal-to-serosal transport of L-valine-acyclovir could be inhibited by L-glycylsarcosine, but not by L-valine, suggesting the involvement of the dipeptide carrier. Also it was found that L-valine-acyclovir inhibits the uptake of cephalexin, a substrate for the oligopeptide transporter. Stability of the esters in either the mucosal or serosal bathing solution is more than 90% after completion of the transport study. However, after transport, the receiver solution contained approximately 90% of acyclovir. Based on these findings it was concluded that absorption of the L-valine ester of acyclovir occurs as a result of uptake by the oligopeptide transporter at the apical cell membrane followed by intracellular hydrolysis of the ester and efflux of acyclovir.

0022-3565/98/2863-1166$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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