CARRIER-MEDIATED INTESTINAL-ABSORPTION OF VALACYCLOVIR, THE L-VALYL ESTER PRODRUG OF ACYCLOVIR - 1 - INTERACTIONS WITH PEPTIDES, ORGANIC-ANIONS AND ORGANIC CATIONS IN RATS

The mechanism of intestinal transport of valacyclovir (VACV), the L-va lyl ester prodrug of acyclovir, was investigated in rats using an ill situ intestinal perfusion technique. VACV demonstrates an oral bioavai lability that is three to five time greater than acyclovir, concentrat ion dependent, and saturable in humans. Homogenate and perfused buffer stability results demonstrated that VACV was increasingly unstable wi th increasing pH. VACV was converted to ACV in a concentration depende nt manner during a single pass through the intestinal segment. Perfusi ons were performed at 37 degrees C, pH 6.5, and under iso-osmotic cond itions (290 +/- 10 mOsm L-1). Intestinal outlet concentrations were co rrected for VACV that was converted to ACV during the perfusion. The e ffective dimensionless intestinal permeability (P-e(),) of VACV was c oncentration dependent, saturable (intrinsic K-m = 1.2 +/- 0.7 mM), an d significantly reduced (P < 0.05) in the presence of peptide analogue s (amoxicillin, ampicillin, cefadroxil, and cephradine), by the organi c anion, p-amino hippuric acid and by the organic cation quinine. VACV transport was not inhibited by classical nucleoside competitive subst rates or inhibitors or by valine. These results suggest that H+-oligop eptide, H+-organic cation, and organic anion transporters are involved in the small-intestinal uptake of VACV. The permeability of VACV in t he colon was very low, indicating that VACV is predominantly absorbed from the small intestine. VACV P-e() was not altered in the presence of glucose-induced convective fluid flow, suggesting that carrier-medi ated, transcellular uptake is the predominant absorption pathway of VA CV in rat small intestine. Based on these results, the oral bioavailab ility of VACV appears to be significantly influenced by the preabsorpt ive conversion of VACV to the poorly absorbed ACV, by the involvement of multiple transporters in VACV small-intestinal uptake, and by the l ow permeability of VACV in the colon. (C) 1998 John Wiley & Sons, Ltd.