Effect of different doses of dexamethasone on the penetration of acyclovir across the blood-brain barrier

Acyclovir (ACV) is a widely used antiviral agent for the treatment of herpes simplex virus encephalitis. Dexamethasone (DEX) is often co-administered as an adjunctive therapy. Tariquidar (TQD), a potent and selective inhibitor of P-glycoprotein, has been demonstrated to enhance the brain accumulation of ACV. This study is designed to systematically investigate the impact of varying DEX dosages on the blood-brain barrier (BBB) transport of ACV, elucidate the mechanisms involved, and evaluate the therapeutic potential of TQD in the management of herpes simplex virus encephalitis. Microdialysis, coupled with high-performance liquid chromatography, was employed to measure unbound ACV concentrations in blood and brain tissue at pre-determined time intervals. The effects of low (0.5 mg/kg), moderate (1 mg/kg), and high (3 mg/kg) doses of DEX, administered continuously for 4 days, on the pharmacokinetic parameters of ACV were evaluated in the presence and absence of tariquidar (TQD, P-glycoprotein inhibitor, 8 mg/kg). The BBB transport of ACV was assessed by calculating the ratio of the area under the unbound brain drug concentration-time curve to the area under the unbound blood drug concentration over time, to reflect changes in the BBB transport (K_p,uu,brain) of ACV. The mean of the area under the unbound brain and blood drug concentration-time curve, and K_p,uu,brain in rats of the solvent control (SC) group were 2674 ± 448 min·μg/mL, 564 ± 136 min·μg/mL, and 20.9 %, respectively. In the low-dose DEX group, ​​the K_{p,uu,brain​} of ACV was 19.5 %, with no statistically significant difference compared with the SC group (P > 0.05). In the moderate- and high-dose DEX groups, the K_{p,uu,brain​} of ACV decreased to 17.0 % and 14.0 %, respectively, with a statistically significant difference compared with the SC group (P < 0.001). Pairwise comparisons further revealed significant differences in the K_p,uu,brain of ACV among different DEX dose groups. Conversely, TQD administration increased the K_p,uu,brain of ACV by 1.40-fold (P < 0.001). The K_p,uu,brain in the TQD plus low-dose DEX group was 27.1 %, significantly higher than that of the SC group (P < 0.001). The K_p,uu,brain of the TQD plus moderate-dose DEX and TQD plus high-dose DEX groups was 21.6 % and 18.4 %, respectively, with no significant difference compared to the SC group (P > 0.05). Low-dose DEX does not significantly alter the BBB transport of ACV. However, moderate to high doses of DEX exhibit a dose-dependent reduction in ACV penetration across the BBB. Co-administration of TQD with DEX counteracts this effect, and even enhancing the BBB transport of ACV.