Abstract
The amino acid prodrug of acyclovir (ACV), valacyclovir (VACV), is an effective antiherpetic drug. Systemic availability of ACV in humans is 3 to 5 times higher after oral administration of VACV. Enhanced bioavailability of VACV has been attributed to its carrier-mediated intestinal absorption via hPEPT1 peptide transporter followed by rapid and complete conversion to ACV. An earlier report suggested that the dipeptide ester prodrugs of ACV possess high affinity toward the intestinal oligopeptide transporter hPEPT1 and therefore seem to be promising candidates in the treatment of oral herpes virus infections. In the present study, we have examined the bioavailability of a series of dipeptide prodrugs of ACV after oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The area under plasma-concentration time curves expressed as minutes microgram milliliter-1 for total concentration of VACV (208.4 ± 41.2), and the dipeptide prodrugs Gly-Val-ACV (GVACV) (416.1 ± 140.9), Val-Val-ACV (VVACV) (147.7 ± 89.3), and Val-Tyr-ACV (VYACV) (180.7 ± 81.2) were significantly higher than that of ACV (21.2 ± 5.2) upon intestinal absorption. Interestingly, the bioavailability of ACV after administration of GVACV was approximately 2-fold higher than VACV. There was significant metabolism by hepatic first pass effect of the dipeptide prodrugs as evident by the higher levels of ACV obtained after systemic absorption compared with intestinal absorption of GVACV and VVACV. The dipeptide prodrugs of ACV exhibited higher systemic availability of regenerated ACV upon oral administration and thus seem to be promising drug candidates in treatment of genital herpes infections.
Footnotes
-
↵1 Current address: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080.
-
ABBREVIATIONS: hPEPT1, human intestinal peptide transporter; ACV, acyclovir; BPHL, biphenyl hydrolase-like; FBS, fetal bovine serum; VACV, valacyclovir; VVACV, valine-valine acyclovir; GVACV, glycine-valine acyclovir; GYACV, glycine-tyrosine acyclovir; VYACV, valine-tyrosine acyclovir; DPBS, Dulbecco's phosphate-buffered saline; HPLC, high-performance liquid chromatography; AUC, area under the curve; CL/F, clearance; MRT, mean residence time; Papp, apparent permeability; HSV, herpes simplex virus.
-
This work was supported by National Institutes of Health Grants R01 EY09171 and R01 EY10659.
-
doi:10.1124/jpet.104.069997.
- Received April 14, 2004.
- Accepted June 14, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|