de Miranda P, Burnette TC, Smith C, Harrington J, Reardon J; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7; 83.

Burroughs Wellcome Co., Research Triangle Park, NC.

The search for an effective prodrug that would provide enhanced acyclovir (ACV) bioavailability led to the synthesis and evaluation of numerous aliphatic and amino acid esters of ACV and to the selection of the L-valyl ester, valacyclovir HCI (VACV), for further preclinical and clinical development. VACV is now in phase III clinical trials for the treatment and prophylaxis of herpes virus infections. Studies in several species, including humans, have demonstrated that VACV is well absorbed and rapidly and efficiently converted to ACV, resulting in a 2- to 5-fold enhancement of ACV bioavailability when compared to oral ACV administration. The mechanism of improved absorption was investigated by measuring ACV and VACV uptake in cynomolgus monkey intestinal brush border membrane vesicles (BBMV). The rate of VACV influx into BBMVs was 6- to 10-fold higher than that of ACV. The influx rate was saturable, transporter- mediated, concentration-dependent, and sodium- and proton- independent. The transporter recognizes dipeptides preferentially to valine and may be stereoselective, since the D-isomer of VACV was very poorly absorbed. The rapid in vivo hydrolysis of VACV to ACV resulted primarily from first-pass intestinal and/or hepatic metabolism and was enzyme-mediated. The putative enzyme, valacyclovir hydrolase (VACVase), was purified from rat liver and characterized as a basic monomeric protein (pl 9.4, 29 kDa). It was also found in rat kidney and intestine, as well as in human liver. Therefore, the enhanced ACV bioavailability after oral VACV is attributed to the improved absorption of VACV via a stereoselective transporter followed by its rapid and efficient hydrolysis to ACV, presumably by VACVase.

Publication Types:

• Meeting Abstracts

Keywords:

• Acyclovir
• Administration, Oral
• Amino Acids
• Animals
• Biological Availability
• Dipeptides
• Esters
• Humans
• Hydrolases
• Hydrolysis
• Intestines
• Membrane Transport Proteins
• Prodrugs
• Rats
• Valine
• valacyclovir

Other ID:

• 95920774

UI: 102213721

From Meeting Abstracts