EFFLUX TRANSPORTER MEDIATED DDIs AT THE BBB ARE UNLIKELY

TAKE HOME MESSAGES FORM THE ITC WHITE PAPERS part 7

One area of much debate is the likelihood of transporter mediated DDIs at the human BBB (Blood-brain barrier). Kalvass et al. summarize the ITC’s position on this matter, which can be simply summarized as: it’s unlikely, at least with currently marketed drugs. Despite preclinical examples of drastically enhanced BBB penetration of drugs in the presence of efflux transporter inhibitors or gene knockout animals, the central argument for the authors’ conclusion comes from calculations based on the fraction excreted (f_e). Using f_e the authors demonstrate that only in cases of near complete inhibition (I/K_i = ∞) of the transporters involved in efflux at the BBB is the fold increase in CNS exposure for a drug significant.

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