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

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

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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Authors and Affiliations

  1. Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China

    Yuheng Shan, Yuying Cen, Ruishu Tan & Jiahua Zhao

  2. Department of Neurology, The First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China

    Yuheng Shan, Yuying Cen, Ruishu Tan, Jiahua Zhao, Jiatang Zhang & Shengyuan Yu

  3. Department of Neurology, Characteristic Medical Centre of People’s Armed Police Force, Tianjin, 300162, People’s Republic of China

    Yuheng Shan

  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

    Yanjin Zhang & Zhiyong Nie

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  1. Yuheng Shan
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Correspondence to Zhiyong Nie or Jiatang Zhang.

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Author contributions

YS, ZN, and JZ were involved in the conception and design; YS, YC, YZ, RT, and JZ performed the experiments and analyzed the samples; YS drafted the manuscript; ZN, JZ, and SY revised the paper. All the authors read and approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work. All authors reviewed the results and approved the final version of the manuscript.

Funding

This work was supported by the Military Medical Technology Youth Program of China [grant number 17QNP060].

Conflicts of interest

The authors declared that they have no conflicts of interest in relation to this work.

Ethics approval

All institutional and national guidelines for the care of the laboratory animals were followed. All experimental protocols involving animals were reviewed and approved by the Committee on Animal Use for Research and Education of the Laboratory Animals Centre, General Hospital of Chinese People’s Liberation Army (Beijing, China).

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The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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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 47, 279–289 (2022). https://doi.org/10.1007/s13318-021-00733-w

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