Metabolism and pharmacokinetics of a double prodrug of ganciclovir in the rat and monkey.
Ganciclovir (GCV), which is used in the treatment of human cytomegalovirus infections, is poorly absorbed orally. A double prodrug of GCV, the dipivalate ester of 6-deoxy-GCV (6-dGCV) (called 6-dGCV-DPiv), was given orally to rats (25 mg/kg) and resulted in a nearly 7-fold enhancement of GCV bioavailability compared with administration of GCV alone and a 2-fold increase compared with administration of 6-dGCV. The prodrug was rapidly hydrolyzed and extensively oxidized by first-pass metabolism in such a way that only GCV, 6-dGCV, and a small amount of the monopivalate ester of 6-dGCV were observed in rat plasma. In cynomolgus monkey was given the prodrug orally (22.5 mg/kg), two additional metabolites were observed--the 8-hydroxy analogs of GCV and dGCV. The double prodrug approach demonstrated the potential for enhanced oral delivery of GCV in humans.
Krasny
H C
HC
Division of Experimental Therapy, Burroughs Wellcome Company.
Beauchamp
L
L
Krenitsky
T A
TA
de Miranda
P
P
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity
C098349:6-deoxyganciclovir dipivalate ester; D000998:Antiviral Agents; D011355:Prodrugs; D015774:Ganciclovir