The ATP-Binding Cassette Transporter-Mediated Efflux Transport of Ganciclovir at the Blood-Brain Barrier.
Journal
European journal of drug metabolism and pharmacokinetics
ISSN: 2107-0180
Titre abrégé: Eur J Drug Metab Pharmacokinet
Pays: France
ID NLM: 7608491
Informations de publication
Date de publication:
04 Jul 2024
04 Jul 2024
Historique:
accepted:
16
06
2024
medline:
4
7
2024
pubmed:
4
7
2024
entrez:
4
7
2024
Statut:
aheadofprint
Résumé
Recent studies have highlighted the key role of the ATP-binding cassette (ABC) transporters, including the P-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and the multi-drug resistance protein 4 (MRP4) in limiting the brain distribution of several antiviral agents. In this study, we investigated whether the inhibition of these transporters increases the permeability of the blood-brain barrier (BBB) to ganciclovir. A microdialysis and high-performance liquid chromatographic method was developed to monitor the concentrations of unbound ganciclovir in the brain interstitial fluid and plasma, with and without the administration of ABC transporter inhibitors. Pharmacokinetic parameters, including the area under the plasma concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC The mean AUC The findings of this study suggest that ABC transporters P-gp, BCRP, and MRP4 mediate the efflux of ganciclovir at the BBB and that the inhibition of these transporters facilitates the penetration of the BBB by ganciclovir.
Sections du résumé
BACKGROUND AND OBJECTIVE
OBJECTIVE
Recent studies have highlighted the key role of the ATP-binding cassette (ABC) transporters, including the P-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and the multi-drug resistance protein 4 (MRP4) in limiting the brain distribution of several antiviral agents. In this study, we investigated whether the inhibition of these transporters increases the permeability of the blood-brain barrier (BBB) to ganciclovir.
METHODS
METHODS
A microdialysis and high-performance liquid chromatographic method was developed to monitor the concentrations of unbound ganciclovir in the brain interstitial fluid and plasma, with and without the administration of ABC transporter inhibitors. Pharmacokinetic parameters, including the area under the plasma concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC
RESULTS
RESULTS
The mean AUC
CONCLUSIONS
CONCLUSIONS
The findings of this study suggest that ABC transporters P-gp, BCRP, and MRP4 mediate the efflux of ganciclovir at the BBB and that the inhibition of these transporters facilitates the penetration of the BBB by ganciclovir.
Identifiants
pubmed: 38963639
doi: 10.1007/s13318-024-00908-1
pii: 10.1007/s13318-024-00908-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : China's Military medical technology youth program
ID : 17QNP060
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
Handley G, Pankow S, Bard JD, Yee R, Nigo M, Hasbun R. Distinguishing cytomegalovirus meningoencephalitis from other viral central nervous system infections. J Clin Virol. 2021;142: 104936.
doi: 10.1016/j.jcv.2021.104936
pubmed: 34352616
Hakki M. Moving past ganciclovir and foscarnet: advances in CMV therapy. Curr Hematol Malig Rep. 2020;15(2):90–102.
doi: 10.1007/s11899-020-00557-6
pubmed: 31981100
pmcid: 7223398
Moyle G, Harman C, Mitchell S, Mathalone B, Gazzard BG. Foscarnet and Ganciclovir in the treatment of CMV retinitis in AIDS patients: a randomised comparison. J Infect. 1992;25(1):21–7.
doi: 10.1016/0163-4453(92)93417-O
pubmed: 1326012
Acosta E, Bowlin T, Brooks J, et al. Advances in the development of therapeutics for cytomegalovirus infections. J Infect Dis. 2020;221(Suppl 1):S32–44.
doi: 10.1093/infdis/jiz493
pubmed: 32134483
pmcid: 7057787
Ljungman P. Cytomegalovirus pneumonia: presentation, diagnosis, and treatment. Semin Respir Infect. 1995;10(4):209–15.
pubmed: 8668848
Reddy SM, Winston DJ, Territo MC, Schiller GJ. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant. 2010;45(6):979–84.
doi: 10.1038/bmt.2010.35
pubmed: 20190836
Ose A, Kusuhara H, Yamatsugu K, et al. P-glycoprotein restricts the penetration of oseltamivir across the blood-brain barrier. Drug Metab Dispos. 2008;36(2):427–34.
doi: 10.1124/dmd.107.018556
pubmed: 18039806
Kaddoumi A, Choi SU, Kinman L, et al. Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid. Drug Metab Dispos. 2007;35(9):1459–62.
doi: 10.1124/dmd.107.016220
pubmed: 17591677
Shan Y, Cen Y, Zhang Y, et al. Acyclovir brain disposition: interactions with P-gp, Bcrp, Mrp2, and Oat3 at the blood–brain barrier. Eur J Drug Metab Pharmacokinet. 2022;47(2):279–89.
doi: 10.1007/s13318-021-00733-w
pubmed: 35112329
Uchida Y, Ohtsuki S, Katsukura Y, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117(2):333–45.
doi: 10.1111/j.1471-4159.2011.07208.x
pubmed: 21291474
Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T. Quantitative atlas of blood–brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. J Pharm Sci. 2013;102(9):3343–55.
doi: 10.1002/jps.23575
pubmed: 23650139
Li M, Si L, Pan H, et al. Excipients enhance intestinal absorption of ganciclovir by P-gp inhibition: assessed in vitro by everted gut sac and in situ by improved intestinal perfusion. Int J Pharm. 2011;403(1–2):37–45.
doi: 10.1016/j.ijpharm.2010.10.017
pubmed: 20969937
Markowicz-Piasecka M, Huttunen J, Montaser A, et al. Ganciclovir and its hemocompatible more lipophilic derivative can enhance the apoptotic effects of methotrexate by inhibiting breast cancer resistance protein (BCRP). Int J Mol Sci. 2021;22(14):7727.
doi: 10.3390/ijms22147727
pubmed: 34299347
pmcid: 8303380
Cen Y, Shan Y, Zhao J, Xu X, Nie Z, Zhang J. Multiple drug transporters contribute to the brain transfer of levofloxacin. CNS Neurosci Ther. 2023;29(1):445–57.
doi: 10.1111/cns.13989
pubmed: 36253925
Dos Santos MF, Dos Santos OF, Boim MA, et al. Nephrotoxicity of acyclovir and ganciclovir in rats: evaluation of glomerular hemodynamics. J Am Soc Nephrol. 1997;8(3):361–7.
doi: 10.1681/ASN.V83361
pubmed: 9071704
Garcia-Varela L, Garcia DV, Kakiuchi T, et al. Pharmacokinetic modeling of (R)-[(11)C]verapamil to measure the P-glycoprotein function in nonhuman primates. Mol Pharm. 2021;18(1):416–28.
doi: 10.1021/acs.molpharmaceut.0c01014
pubmed: 33315404
Bauer M, Zeitlinger M, Karch R, et al. Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood–brain barrier: a comparison with rat data. Clin Pharmacol Ther. 2012;91(2):227–33.
doi: 10.1038/clpt.2011.217
pubmed: 22166851
Wanek T, Kuntner C, Bankstahl JP, et al. A novel PET protocol for visualization of breast cancer resistance protein function at the blood–brain barrier. J Cereb Blood Flow Metab. 2012;32(11):2002–11.
doi: 10.1038/jcbfm.2012.112
pubmed: 22828996
pmcid: 3493998
Xia W, Zhang H, Pan Z, et al. Inhibition of MRP4 alleviates sepsis-induced acute lung injury in rats. Int Immunopharmacol. 2019;72:211–7.
doi: 10.1016/j.intimp.2019.04.009
pubmed: 30995593
Hou J, Liu Q, Li Y, Sun H, Zhang J. An in vivo microdialysis study of FLZ penetration through the blood–brain barrier in normal and 6-hydroxydopamine induced Parkinson’s disease model rats. Biomed Res Int. 2014;2014: 850493.
doi: 10.1155/2014/850493
pubmed: 25045708
pmcid: 4090575
Loryan I, Reichel A, Feng B, et al. Unbound brain-to-plasma partition coefficient, K(p, uu, brain)—a game changing parameter for CNS drug discovery and development. Pharm Res. 2022;39(7):1321–41.
doi: 10.1007/s11095-022-03246-6
pubmed: 35411506
pmcid: 9246790
Hammarlund-Udenaes M, Friden M, Syvanen S, Gupta A. On the rate and extent of drug delivery to the brain. Pharm Res. 2008;25(8):1737–50.
doi: 10.1007/s11095-007-9502-2
pubmed: 18058202
Gynther M, Kaariainen TM, Hakkarainen JJ, et al. Brain pharmacokinetics of ganciclovir in rats with orthotopic BT4C glioma. Drug Metab Dispos. 2015;43(1):140–6.
doi: 10.1124/dmd.114.059840
pubmed: 25349125
Greig NH, Sweeney DJ, Rapoport SI. Inability of dimethyl sulfoxide to increase brain uptake of water-soluble compounds: implications to chemotherapy for brain tumors. Cancer Treat Rep. 1985;69(3):305–12.
pubmed: 3978658
Yang J, Betterton RD, Williams EI, et al. High-dose acetaminophen alters the integrity of the blood–brain barrier and leads to increased CNS uptake of codeine in rats. Pharmaceutics. 2022;14(5):949.
doi: 10.3390/pharmaceutics14050949
pubmed: 35631535
pmcid: 9144323
Adachi M, Sampath J, Lan LB, et al. Expression of MRP4 confers resistance to ganciclovir and compromises bystander cell killing. J Biol Chem. 2002;277(41):38998–9004.
doi: 10.1074/jbc.M203262200
pubmed: 12105214
Kuntner C, Bankstahl JP, Bankstahl M, et al. Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood–brain barrier using (R)-[(11)C]verapamil PET. Eur J Nucl Med Mol Imaging. 2010;37(5):942–53.
doi: 10.1007/s00259-009-1332-5
pubmed: 20016890
Breuil L, Goutal S, Marie S, et al. Comparison of the blood–brain barrier transport and vulnerability to P-glycoprotein-mediated drug–drug interaction of domperidone versus metoclopramide assessed using in vitro assay and PET imaging. Pharmaceutics. 2022;14(8):1658.
doi: 10.3390/pharmaceutics14081658
pubmed: 36015284
pmcid: 9412994
Morris ME, Rodriguez-Cruz V, Felmlee MA. SLC and ABC transporters: expression, localization, and species differences at the blood–brain and the blood-cerebrospinal fluid barriers. AAPS J. 2017;19(5):1317–31.
doi: 10.1208/s12248-017-0110-8
pubmed: 28664465