Relationship Between Exposure and Nonspecific Binding of Thirty-Three Central Nervous System Drugs in Mice

Abstract

ABSTRACT:Unbound fractions in mouse brain and plasma were determined for 31 structurally diverse central nervous system (CNS) drugs and two active metabolites. Three comparisons were made between in vitro binding and in vivo exposure data, namely: 1) mouse brainto-plasma exposure versus unbound plasma-to-unbound brain fraction ratio (fu plasma /fu brain ), 2) cerebrospinal fluid-to-brain exposure versus unbound brain fraction (fu brain ), and 3) cerebrospinal fluid-to-plasma exposure versus unbound plasma fraction (fu plasma ). Unbound fraction data were within 3-fold of in vivo exposure ratios for the majority of the drugs examined (i.e., 22 of 33), indicating a predominately free equilibrium across the blood-brain and blood-CSF barriers. Some degree of distributional impairment at either the blood-CSF or the blood-brain barrier was indicated for 8 of the 11 remaining drugs (i.e., carbamazepine, midazolam, phenytoin, sulpiride, thiopental, risperidone, 9-hydroxyrisperidone, and zolpidem). In several cases, the indicated distributional impairment is consistent with other independent literature reports for these drugs. Through the use of this approach, it appears that most CNS-active agents freely equilibrate across the blood-brain and blood-CSF barriers such that unbound drug concentrations in brain approximate those in the plasma. However, these results also support the intuitive concept that distributional impairment does not necessarily preclude CNS activity.

Prediction of the Clinical SUV Ratio in Amyloid PET Imaging Using a Biomathematic Modeling Approach Toward the Efficient Development of a Radioligand

“…For each radioligand, f p and f ND were predicted using the datasets shown in Figure 2. Even though there was inconsistent use of lipophilicity for estimation of f p and f ND between our study (which used Moriguchi logP) and the studies of Wan et al (23) and Mauer et al (24) (which used clogP), we observed positive correlations between predicted and clinical k 2 in the healthy and AD groups (R 2 5 0.81 and 0.85, respectively) (Fig. 3B).…”

“…Regression Relationship of f P vs. f ND and f ND vs. logP Figure 2A shows the relationships between in silico lipophilicity and in vitro f ND , and Figure 2B shows the relationships between in vitro f ND and f P using the datasets of Wan et al (23) and Maurer et al (24). Good correlations were observed between lipophilicity and f ND and between f ND and f P (R 2 5 0.78 and 0.80, respectively).…”

“…This result supports the possibility that use of the Moriguchi logP without in vitro experiments for f p and f ND estimation can be applied to other amyloid radioligands. There have been several studies with reported data sets for in silico logP, in vitro f p , and f ND for CNS drugs or radioligands (17,23,24,29). The data sets selected for use may change the predicted f P and f ND .…”

“…f P and f ND were estimated from in vitro binding experiments using mouse brain and plasma and the in silico lipophilicity of 24 CNS drugs (e.g., risperidone, haloperidol, and fluvoxamine) reported by Wan et al (23) and Maurer et al (24). The datasets were obtained from references, and then the regression relationships for clogP versus f ND and f ND versus f P were determined.…”

Progress in Brain Penetration Evaluation in Drug Discovery and Development

“…According to eq. 2, K p,free can be calculated from K p , f u,plasma , and f u,brain , where K p can be determined from in vivo studies and f u,plasma and f u,brain can be estimated using in vitro equilibrium dialysis approaches with plasma and brain tissue homogenate, respectively (Maurer et al, 2005). Recently, we examined the correlation between the K p,free determined using microdialysis and the K p,free estimated from eq.…”