2. Academic Validation
  3. Acyclovir Brain Disposition: Interactions with P-gp, Bcrp, Mrp2, and Oat3 at the Blood-Brain Barrier

Acyclovir Brain Disposition: Interactions with P-gp, Bcrp, Mrp2, and Oat3 at the Blood-Brain Barrier

  • Eur J Drug Metab Pharmacokinet. 2022 Mar;47(2):279-289. doi: 10.1007/s13318-021-00733-w.
Yuheng Shan 1 2 3,  Yuying Cen 1 2,  Yanjin Zhang 4,  Ruishu Tan 1 2,  Jiahua Zhao 1 2,  Zhiyong Nie 5,  Jiatang Zhang 6,  Shengyuan Yu 2
Affiliations

Affiliations

  • 1 Medical School of Chinese PLA, Beijing, 100853, People's Republic of China.
  • 2 Department of Neurology, The First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
  • 3 Department of Neurology, Characteristic Medical Centre of People's Armed Police Force, Tianjin, 300162, People's Republic of China.
  • 4 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, People's Republic of China.
  • 5 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, People's Republic of China. niezhiyong2018@sina.com.
  • 6 Department of Neurology, The First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China. zjt1128@aliyun.com.
PMID: 35112329 DOI: 10.1007/s13318-021-00733-w
Abstract

Background and objective: Acyclovir is effective in treating herpes simplex virus infections of the central nervous system. The purpose of this study was to investigate the interactions between acyclovir and the efflux pumps P-glycoprotein (P-gp), breast Cancer resistance protein (BCRP), multidrug resistance protein 2 (Mrp2), and organic anion transporter 3 (Oat3) at the blood-brain barrier (BBB).

Methods: Acyclovir concentrations in the blood and brain were evaluated by microdialysis and high-performance liquid chromatography. Acyclovir pharmacokinetic parameters, including the area under the unbound blood concentration-time curve (AUCu,blood), the area under the unbound brain concentration-time curve (AUCu,brain), and the ratio of AUCu,brain to AUCu,blood (Kp.uu.brain), were evaluated in the presence and absence of elacridar (P-gp/BCRP Inhibitor, 7.5 mg/kg), tariquidar (P-gp/BCRP Inhibitor, 7.5 mg/kg), MK571 (Mrp2 inhibitor, 7.5 mg/kg), cyclosporine (P-gp/BCRP/Mrp2 inhibitor, 25 mg/kg), and probenecid (Oat3 inhibitor, 50 mg/kg).

Results: The average AUCu,blood, AUCu,brain, and Kp.uu.brain in rats who received acyclovir (25 mg/kg, intravenous) alone were 1377.7 min · μg/ml, 435.4 min · μg/ml, and 31.6%, respectively. Probenecid drastically increased the AUCu,blood of acyclovir 1.73-fold, whereas coadministration with elacridar, tariquidar, MK571, and cyclosporine did not alter the blood pharmacokinetic parameters of acyclovir. Elacridar, tariquidar, MK571, cyclosporine, and probenecid significantly increased the AUCu,brain of acyclovir 1.51-, 1.54-, 1.47-, 1.95-, and 2.34-fold, respectively. Additionally, the Kp.uu.brain of acyclovir markedly increased 1.48-, 1.63-, 1.39-, 1.90-, and 1.35-fold following elacridar, tariquidar, MK571, cyclosporine, and probenecid administration, respectively.

Conclusion: The present study demonstrated that P-gp, BCRP, Mrp2, and Oat3 inhibition increased the penetration of acyclovir across the BBB, supporting the hypothesis that these efflux pumps restrict the distribution of acyclovir in the brain.

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