title: Pharmacokinetic studies and LC-MS/MS method development of ganciclovir and dipeptide monoester prodrugs in Sprague Dawley rats.
abstract: Ganciclovir (GCV) is utilized as an anti-herpetic agent. Reports from our laboratory have suggested that dipeptide ester prodrugs of GCV exhibit high affinity towards the oligopeptide transporter hPEPT1 and therefore seem to be promising candidates for the treatment of oral herpes virus infections. In this study, we have examined the bio-availability of a dipeptide prodrug of GCV after oral administration in jugular cannulated Sprague-Dawley rats. A new bio-analytical method was developed with Q-TRAP liquid chromatography tandem mass spectroscopy (LC-MS/MS) for simultaneous analysis of GCV, Valine-GCV (VGCV) and Tyrosine-Valine-GCV (YVGCV). Acyclovir (ACV) was used as an internal standard in the analysis. Area under plasma-concentration time curves for total concentration of GCV after oral administration of YVGCV was found to be approximately 200 % more than that of GCV following intestinal absorption. A complete conversion of the dipeptide prodrug (YVGCV) to parent compound, GCV, by hepatic first-pass metabolism was evident due to the absence of intermediate metabolite VGCV and administered prodrug YVGCV. The dipeptide prodrugs of GCV exhibit higher systemic availability of regenerated GCV upon oral administration and thus seem to be promising drug candidate in the treatment of systemic herpes infections.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO, 64108, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Gunda
authors.forename: Ravinder
authors.initials: R
authors.lastname: Earla
authors.forename: Kishore
authors.initials: K
authors.lastname: Cholkar
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D000212:Acyclovir / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000502:physiology; D002853:Chromatography, Liquid / Q000379:methods; D004151:Dipeptides / Q000493:pharmacokinetics*; D004952:Esters / Q000493:pharmacokinetics*; D015774:Ganciclovir / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000502:physiology; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D004151:Dipeptides; D004952:Esters; D011355:Prodrugs; D015774:Ganciclovir; D000212:Acyclovir