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How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors

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Abstract

The lack of effective chemotherapeutic agents for the treatment of brain tumors is a serious unmet medical need. This can be attributed, in part, to inadequate delivery through the blood-brain barrier (BBB) and the tumor-cell barrier, both of which have active efflux transporters that can restrict the transport of many potentially effective agents for both primary and metastatic brain tumors. This review briefly summarizes the components and function of the normal BBB with respect to drug penetration into the brain and the alterations in the BBB due to brain tumor that could influence drug delivery. Depending on what is rate-limiting a compound’s distribution, the limited permeability across the BBB and the subsequent delivery into the tumor cell can be greatly influenced by efflux transporters and these are discussed in some detail. Given these complexities, it is necessary to quantify the extent of brain distribution of the active (unbound) drug to compare across compounds and to inform potential for use against brain tumors. In this regard, the metric, Kp,uu, a brain-to-plasma unbound partition coefficient, is examined and its current use is discussed. However, the extent of active drug delivery is not the only determinant of effective therapy. In addition to Kp,uu, drug potency is an important parameter that should be considered alongside drug delivery in drug discovery and development processes. In other words, to answer the question - How much is enough? - one must consider how much can be delivered with how much needs to be delivered.

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Funding

National Institutes of Health National Cancer Institute Grant U19-CA264362, U01-CA227954, National Brain Tumor Society AWD0006946 / 21-004061. The first author was partially supported by the Ronald J. Sawchuk Fellowship in Pharmacokinetics, Rory P. Remmel and Cheryl L. Zimmerman Fellowship in Drug Metabolism and Pharmacokinetics, and Bighley Graduate Fellowship.

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  1. Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    Wenjuan Zhang, Ju-Hee Oh, Wenqiu Zhang, Sneha Rathi, Jiayan Le, Surabhi Talele & William F. Elmquist

  2. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA

    Jann N. Sarkaria

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Zhang, W., Oh, JH., Zhang, W. et al. How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors. Pharm Res 40, 2731–2746 (2023). https://doi.org/10.1007/s11095-023-03574-1

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