Skip to main content

Advertisement

Springer Nature Link
Log in

Pharmacokinetic studies and LC–MS/MS method development of ganciclovir and dipeptide monoester prodrugs in Sprague Dawley rats

  • Original Paper
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Explore related subjects

Discover the latest articles, news and stories from top researchers in related subjects.

References

  • Acosta EP, Fletcher CV (1997) Valacyclovir. Ann Pharmacother 31(2):185–191

    CAS  PubMed  Google Scholar 

  • Anand BS, Mitra AK (2002) Mechanism of corneal permeation of L-valyl ester of acyclovir: targeting the oligopeptide transporter on the rabbit cornea. Pharm Res 19(8):1194–1202

    Article  CAS  PubMed  Google Scholar 

  • Atluri H, Anand BS, Patel J, Mitra AK (2004) Mechanism of a model dipeptide transport across blood-ocular barriers following systemic administration. Exp Eye Res 78(4):815–822

    Article  CAS  PubMed  Google Scholar 

  • Balfour HH Jr, Kelly JM, Suarez CS, Heussner RC, Englund JA, Crane DD, McGuirt PV, Clemmer AF, Aeppli DM (1990) Acyclovir treatment of varicella in otherwise healthy children. J Pediatr 116(4):633–639

    Article  PubMed  Google Scholar 

  • Bean B, Aeppli D (1985) Adverse effects of high-dose intravenous acyclovir in ambulatory patients with acute herpes zoster. J Infect Dis 151(2):362–365

    Article  CAS  PubMed  Google Scholar 

  • Black ME, Newcomb TG, Wilson HM, Loeb LA (1996) Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc Natl Acad Sci USA 93(8):3525–3529

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cheng YC, Grill SP, Dutschman GE, Nakayama K, Bastow KF (1983) Metabolism of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a new anti-herpes virus compound, in herpes simplex virus-infected cells. J Biol Chem 258(20):12460–12464

    CAS  PubMed  Google Scholar 

  • Cheng YC, Grill SP, Dutschman GE, Frank KB, Chiou JF, Bastow KF, Nakayama K (1984) Effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a new antiherpesvirus compound, on synthesis of macromolecules in herpes simplex virus-infected cells. Antimicrob Agents Chemother 26(3):283–288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cholkar K, Patel SP, Vadlapudi AD, Mitra AK (2013) Novel strategies for anterior segment ocular drug delivery. J Ocular Pharmacol Ther 29(2):106–123. doi:10.1089/jop.2012.0200

    Article  CAS  Google Scholar 

  • Crumpacker CS (1996) Ganciclovir. N Engl J Med 335(10):721–729. doi:10.1056/NEJM199609053351007

    Article  CAS  PubMed  Google Scholar 

  • De Clercq E (1993) Antivirals for the treatment of herpesvirus infections. J Antimicrob Chemother 32(Suppl A):121–132

    Article  PubMed  Google Scholar 

  • Earla R, Cholkar K, Gunda S, Earla RL, Mitra AK (2012) Bioanalytical method validation of rapamycin in ocular matrix by QTRAP LC-MS/MS: application to rabbit anterior tissue distribution by topical administration of rapamycin nanomicellar formulation. J Chromatogr B Anal Technol Biomed Life Sci 908:76–86. doi:10.1016/j.jchromb.2012.09.014

    Article  CAS  Google Scholar 

  • Earla R, Ande A, McArthur C, Kumar A, Kumar S (2014) Enhanced nicotine metabolism in HIV-1-positive smokers compared with HIV-negative smokers: simultaneous determination of nicotine and its four metabolites in their plasma using a simple and sensitive electrospray ionization liquid chromatography-tandem mass spectrometry technique. Drug Metab Dispos 42(2):282–293. doi:10.1124/dmd.113.055186

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ernst ME, Franey RJ (1998) Acyclovir- and ganciclovir-induced neurotoxicity. Ann Pharmacother 32(1):111–113

    Article  CAS  PubMed  Google Scholar 

  • Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME (1997) Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 337(16):1105–1111. doi:10.1056/NEJM199710163371601

    Article  CAS  PubMed  Google Scholar 

  • Frank KB, Chiou J-F, Cheng Y (1984) Interaction of herpes simplex virus induced DNA polymerase with 9-(1,3-dihydroxy-2-propoxymethyl)guanine triphosphate. J Biol Chem 259:1566–1569

    CAS  PubMed  Google Scholar 

  • Freeman S, Gardiner JM (1996) Acyclic nucleosides as antiviral compounds. Mol Biotechnol 5(2):125–137. doi:10.1007/BF02789061

    Article  CAS  PubMed  Google Scholar 

  • Gnann JW Jr, Barton NH, Whitley RJ (1983) Acyclovir: mechanism of action, pharmacokinetics, safety and clinical applications. Pharmacotherapy 3(5):275–283

    CAS  PubMed  Google Scholar 

  • Goldmeier D, Johnson A, Byrne M, Barton S (1988) Psychosocial implications of recurrent genital herpes simplex virus infection. Genitourin Med 64(5):327–330

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hamzeh FM, Lietman PS (1991) Intranuclear accumulation of subgenomic noninfectious human cytomegalovirus DNA in infected cells in the presence of ganciclovir. Antimicrob Agents Chemother 35(9):1818–1823

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hamzeh FM, Lietman PS, Gibson W, Hayward GS (1990) Identification of the lytic origin of DNA replication in human cytomegalovirus by a novel approach utilizing ganciclovir-induced chain termination. J Virol 64(12):6184–6195

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hellden A, Lycke J, Vander T, Svensson JO, Odar-Cederlof I, Stahle L (2006) The aciclovir metabolite CMMG is detectable in the CSF of subjects with neuropsychiatric symptoms during aciclovir and valaciclovir treatment. J Antimicrob Chemother 57(5):945–949. doi:10.1093/jac/dkl067

    Article  CAS  PubMed  Google Scholar 

  • Luby JP, Gnann JW Jr, Alexander WJ, Hatcher VA, Friedman-Kien AE, Klein RJ, Keyserling H, Nahmias A, Mills J, Schachter J et al (1984) A collaborative study of patient-initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J Infect Dis 150(1):1–6

    Article  CAS  PubMed  Google Scholar 

  • Majumdar S, Gunda S, Mitra A (2003) Functional expression of a sodium dependent nucleoside transporter on rabbit cornea: role in corneal permeation of acyclovir and idoxuridine. Curr Eye Res 26(3–4):175–183

    Article  PubMed  Google Scholar 

  • Majumdar S, Nashed YE, Patel K, Jain R, Itahashi M, Neumann DM, Hill JM, Mitra AK (2005) Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations. J Ocular Pharmacol Ther 21(6):463–474

    Article  CAS  Google Scholar 

  • Manne S, Sandler I (1984) Coping and adjustment to genital herpes. J Behav Med 7(4):391–410

    Article  CAS  PubMed  Google Scholar 

  • Martin JC, Dvorak CA, Smee DF, Matthews TR, Verheyden JP (1983) 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: a new potent and selective antiherpes agent. J Med Chem 26(5):759–761

    Article  CAS  PubMed  Google Scholar 

  • Moolten FL, Wells JM (1990) Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 82(4):297–300

    Article  CAS  PubMed  Google Scholar 

  • Nichols WG, Boeckh M (2000) Recent advances in the therapy and prevention of CMV infections. J Clini Virol 16(1):25–40

    Article  CAS  Google Scholar 

  • Perazella MA (1999) Crystal-induced acute renal failure. Am J Med 106(4):459–465

    Article  CAS  PubMed  Google Scholar 

  • Perry CM, Faulds D (1996) Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs 52(5):754–772

    Article  CAS  PubMed  Google Scholar 

  • Razonable RR (2011) Antiviral drugs for viruses other than human immunodeficiency virus. Mayo Clin Proc 86(10):1009–1026

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smee DF, Martin JC, Verheyden JP, Matthews TR (1983) Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Antimicrob Agents Chemother 23(5):676–682

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smythe WR, Hwang HC, Elshami AA, Amin KM, Eck SL, Davidson BL, Wilson JM, Kaiser LR, Albelda SM (1995) Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene. Ann Surg 222(1):78–86

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tirucherai GS, Dias C, Mitra AK (2002) Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design. J Ocular Pharmacol Ther 18(6):535–548. doi:10.1089/108076802321021081

    Article  CAS  Google Scholar 

  • Vile RG, Hart IR (1993) Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA. Cancer Res 53(17):3860–3864

    CAS  PubMed  Google Scholar 

  • Wade JC, Meyers JD (1983) Neurologic symptoms associated with parenteral acyclovir treatment after marrow transplantation. Ann Intern Med 98(6):921–925

    Article  CAS  PubMed  Google Scholar 

  • Wallace MR, Bowler WA, Murray NB, Brodine SK, Oldfield EC 3rd (1992) Treatment of adult varicella with oral acyclovir. A randomized, placebo-controlled trial. Ann Intern Med 117(5):358–363

    Article  CAS  PubMed  Google Scholar 

  • Wiltshire H, Hirankarn S, Farrell C, Paya C, Pescovitz MD, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Valganciclovir Solid Organ Transplant Study G (2005) Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Clin Pharmacokinet 44(5):495–507

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by NIH grants RO1 EY 09171-14 and RO1 EY 10659-11. We thank Rajneet Oberoi for her support and Hoffman La Roche (Nutley, NJ) for their generous gift of ganciclovir.

Conflict of interest

Authors have no conflict.

Author information

Authors and Affiliations

  1. Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO, 64108, USA

    Sriram Gunda, Ravinder Earla, Kishore Cholkar & Ashim K. Mitra

Authors
  1. Sriram Gunda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ravinder Earla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kishore Cholkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ashim K. Mitra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashim K. Mitra.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gunda, S., Earla, R., Cholkar, K. et al. Pharmacokinetic studies and LC–MS/MS method development of ganciclovir and dipeptide monoester prodrugs in Sprague Dawley rats. Eur J Drug Metab Pharmacokinet 40, 325–334 (2015). https://doi.org/10.1007/s13318-014-0200-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-014-0200-2

Keywords

Search

Navigation