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Effect of P-glycoprotein Inhibition on the Penetration of Ceftriaxone Across the Blood–Brain Barrier

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Abstract

Recent studies indicate that inhibition of the efflux transporter P-glycoprotein (P-gp) at the blood–brain barrier (BBB) may represent a putative strategy to increase the BBB penetration of several antibiotics. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of ceftriaxone (CFX) across the BBB. Blood and brain microdialysis in rats was used to monitor blood and brain unbound CFX concentrations following intravenous administration (50 mg/kg), with or without pretreatment with one of the P-gp inhibitors, cyclosporin A (6.25, 12.5, 25 mg/kg) or verapamil (5, 10, 20 mg/kg). An inhibitory effect was demonstrated by an increase in the ratio of unbound brain to unbound blood concentration (Kp.uu.brain) of CFX. The concentrations of CFX in blood and brain from 0 to 180 min after intravenous administration (CFX, 50 mg/kg) ranged from 3 to 40 μg/ml and 1 to 10 μg/ml, respectively. The Kp.uu.brain of CFX was 24.74 ± 1.34%. Pretreatment with cyclosporin A increased the brain concentration and the Kp.uu.brain of CFX in a dose-dependent manner. However, pretreatment with verapamil increased the brain concentration of CFX but not the Kp.uu.brain. The present data shows that CFX might be a substrate of P-gp efflux transporter at the BBB and P-gp inhibition might enhance the brain concentration of CFX. Future studies involving more selective P-gp inhibitors or knockout mouse models should be conducted to specifically elucidate the impact of P-gp inhibition on penetration of CFX across the BBB.

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Acknowledgements

This work was supported by the Military medical technology youth program of China [Grant number 17QNP060].

Funding

This work was supported by the Military medical technology youth program of China [Grant Number 17QNP060].

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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, No. 28, Fuxing Road, 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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Contributions

SYH performed all experiments and wrote the manuscript; CYY, ZYJ, TRS, and ZJH helped with the animal experiments study; ZJT, NZY, and YSY conducted and supervised the whole experiments. All authors read and approved the final manuscript.

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Correspondence to Zhiyong Nie or Jiatang Zhang.

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Animal care and use were in accordance with the NIH Guide for the Care and Use of Laboratory Animals (NIH Publication 85–23, Bethesda, MD) 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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Shan, Y., Cen, Y., Zhang, Y. et al. Effect of P-glycoprotein Inhibition on the Penetration of Ceftriaxone Across the Blood–Brain Barrier. Neurochem Res 47, 634–643 (2022). https://doi.org/10.1007/s11064-021-03472-1

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