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Metabolism and pharmacokinetics of a double prodrug of ganciclovir in the rat and monkey.
Drug Metab Dispos 1995; 23(11):1242-7DM

Abstract

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.

Authors+Show Affiliations

Division of Experimental Therapy, Burroughs Wellcome Company.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

8591725

Citation

Krasny, H C., et al. "Metabolism and Pharmacokinetics of a Double Prodrug of Ganciclovir in the Rat and Monkey." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 23, no. 11, 1995, pp. 1242-7.
Krasny HC, Beauchamp L, Krenitsky TA, et al. Metabolism and pharmacokinetics of a double prodrug of ganciclovir in the rat and monkey. Drug Metab Dispos. 1995;23(11):1242-7.
Krasny, H. C., Beauchamp, L., Krenitsky, T. A., & de Miranda, P. (1995). Metabolism and pharmacokinetics of a double prodrug of ganciclovir in the rat and monkey. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 23(11), pp. 1242-7.
Krasny HC, et al. Metabolism and Pharmacokinetics of a Double Prodrug of Ganciclovir in the Rat and Monkey. Drug Metab Dispos. 1995;23(11):1242-7. PubMed PMID: 8591725.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolism and pharmacokinetics of a double prodrug of ganciclovir in the rat and monkey. AU - Krasny,H C, AU - Beauchamp,L, AU - Krenitsky,T A, AU - de Miranda,P, PY - 1995/11/1/pubmed PY - 1995/11/1/medline PY - 1995/11/1/entrez SP - 1242 EP - 7 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 23 IS - 11 N2 - 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/8591725/Metabolism_and_pharmacokinetics_of_a_double_prodrug_of_ganciclovir_in_the_rat_and_monkey_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8591725 DB - PRIME DP - Unbound Medicine ER -