Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery

Abstract Relative plasma, brain and cerebrospinal fluid (CSF) exposures and unbound fractions in plasma and brain were examined for 18 proprietary compounds in rats. The relationship between in vivo brain‐to‐plasma ratio and in vitro plasma‐to‐brain unbound fraction (fu) was examined. In addition, plasma fu and brain fu were examined for their relationship to in vivo CSF‐to‐plasma and CSF‐to‐brain ratios, respectively. Findings were delineated based on the presence or absence of active efflux. Finally, the same comparisons were examined in FVB vs. MDR 1a/1b knockout mice for a selected P‐glycoprotein (Pgp) substrate. For the nine compounds without indications of active efflux, predictive correlations were observed between ratios of brain‐to‐plasma exposure and plasma‐to‐brain fu ( r 2 = 0.98), CSF‐to‐brain exposure vs. brain fu ( r 2 = 0.72), and CSF‐to‐plasma exposure vs. plasma fu ( r 2 = 0.82). For the nine compounds with indications of active efflux, nonspecific binding data tended to over predict the brain‐to‐plasma and CSF‐to‐plasma exposure ratios. Interestingly, CSF‐to‐brain exposure ratio was consistently under predicted by brain fu for this set. Using a select Pgp substrate, it was demonstrated that the brain‐to‐plasma exposure ratio was identical to that predicted by plasma‐to‐brain fu ratio in MDR 1a/1b knockout mice. In FVB mice, plasma‐to‐brain fu over predicted brain‐to‐plasma exposure ratio to the same degree as the difference in brain‐to‐plasma exposure ratio between MDR 1a/1b and FVB mice. Consistent results were obtained in rats, suggesting a similar kinetic behavior between species. These data illustrate how an understanding of relative tissue binding (plasma, brain) can allow for a quantitative examination of active processes that determine CNS exposure. The general applicability of this approach offers advantages over species‐ and mechanism‐specific approaches. Copyright © 2002 John Wiley & Sons, Ltd.