The ATP-Binding Cassette Transporter-Mediated Efflux Transport of Ganciclovir at the Blood-Brain Barrier.

Background and 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: 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_0-t,plasma), the area under the brain interstitial fluid concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC_0-t,brain), and the unbound brain-to-plasma concentration ratio (K_p,uu,brain) were calculated.

Results: The mean AUC_0-t,plasma, AUC_0-t,brain, and K_p,uu,brain in rats who received ganciclovir (30 mg/kg, intraperitoneal) alone were 1090 min·µg/mL, 150 min·µg/mL, and 14%, respectively. After the administration of tariquidar (inhibitor of P-gp), Ko143 (inhibitor of BCRP), or MK-571 (inhibitor of MRP4), the K_p,uu,brain of ganciclovir increased to 31 ± 2.1%, 26 ± 1.3%, and 32 ± 2.0%, respectively.

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.