Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir. 1. Interactions with peptides, organic anions and organic cations in rats

Abstract

The mechanism of intestinal transport of valacyclovir (VACV), the L‐valyl ester prodrug of acyclovir, was investigated in rats using an in situ intestinal perfusion technique. VACV demonstrates an oral bioavailability that is three to five time greater than acyclovir, concentration dependent, and saturable in humans. Homogenate and perfused buffer stability results demonstrated that VACV was increasingly unstable with increasing pH. VACV was converted to ACV in a concentration dependent manner during a single pass through the intestinal segment. Perfusions were performed at 37°C, pH 6.5, and under iso‐osmotic conditions (290±10 mOsm L−1). Intestinal outlet concentrations were corrected for VACV that was converted to ACV during the perfusion. The effective dimensionless intestinal permeability (Pe*) of VACV was concentration dependent, saturable (intrinsic Km = 1.2±0.7 mM), and significantly reduced (p <0.05) in the presence of peptide analogues (amoxicillin, ampicillin, cefadroxil, and cephradine), by the organic anion, p ‐amino hippuric acid and by the organic cation quinine. VACV transport was not inhibited by classical nucleoside competitive substrates or inhibitors or by valine. These results suggest that H+–oligopeptide, H+–organic cation, and organic anion transporters are involved in the small‐intestinal uptake of VACV. The permeability of VACV in the colon was very low, indicating that VACV is predominantly absorbed from the small intestine. VACV Pe* was not altered in the presence of glucose‐induced convective fluid flow, suggesting that carrier‐mediated, transcellular uptake is the predominant absorption pathway of VACV in rat small intestine. Based on these results, the oral bioavailability of VACV appears to be significantly influenced by the preabsorptive conversion of VACV to the poorly absorbed ACV, by the involvement of multiple transporters in VACV small‐intestinal uptake, and by the low permeability of VACV in the colon. © 1998 John Wiley & Sons, Ltd.

Valganciclovir Results in Improved Oral Absorption of Ganciclovir in Liver Transplant Recipients

“…The addition of the valine moiety dramatically increases the absorption, by approximately a factor of 10. The mechanism of the increased bioavailability most likely involves a peptide-mediated active transport, as has been shown for valacyclovir (9,21). The relative bioavailability of 900 mg of VGC provided drug exposure equivalent to that provided by a 5-mg/kg dose of i.v.…”

Direct Evidence that Saquinavir Is Transported by Multidrug Resistance-Associated Protein (MRP1) and Canalicular Multispecific Organic Anion Transporter (MRP2)

“…In addition, a fluorescent saquinavir derivative was previ- ously shown to be transported by MRP2 (14). Since it is known that changes in chemical structure, including derivatization, may alter transport characteristics (23), this does not provide evidence that saquinavir is translocated by MRP2. Although suggestive of saquinavir transport by MRP2, the derivatization of saquinavir may have potentially confounded the study result by creating a new molecule with transport properties different from those of the parent saquinavir molecule.…”

Herpes Zoster and Immunogenicity and Safety of Zoster Vaccines in Transplant Patients: A Narrative Review of the Literature

“…Valacyclovir is a prodrug of acyclovir with three to five times higher oral bioavailability than acyclovir ( 44 ), and it was approved for use as an additional treatment for herpes virus infections in the USA in 1995 ( 45 ). The convenient dosing schedule (1,000 mg three times daily) and quicker cessation of pain makes valacyclovir more efficacious than acyclovir in treating acute HZ ( 46 ).…”