Improved Measurement of Drug Exposure in the Brain Using Drug-Specific Correction for Residual Blood

Abstract

A major challenge associated with the determination of the unbound brain-to-plasma concentration ratio of a drug (K p,uu,brain ), is the error associated with correction for the drug in various vascular spaces of the brain, i.e., in residual blood. The apparent brain vascular spaces of plasma water (V water , 10.3 lL/g brain), plasma proteins (V protein , 7.99 lL/g brain), and the volume of erythrocytes (V er , 2.13 lL/g brain) were determined and incorporated into a novel, drug-specific correction model that took the drug-unbound fraction in the plasma (f u,p ) into account. The correction model was successfully applied for the determination of K p,uu,brain for indomethacin, loperamide, and moxalactam, which had potential problems associated with correction. The influence on correction of the drug associated with erythrocytes was shown to be minimal. Therefore, it is proposed that correction for residual blood can be performed using an effective plasma space in the brain (V eff ), which is calculated from the measured f u,p of the particular drug as well as from the estimates of V water and V protein , which are provided in this study. Furthermore, the results highlight the value of determining K p,uu,brain with statistical precision to enable appropriate interpretation of brain exposure for drugs that appear to be restricted to the brain vascular spaces.

Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats

“…Unbound fraction of TREO and S,S-EBDM determined in vitro in the rat plasma and brain homogenate was practically equal to 1, regardless of the analytes concentration applied ( Table 2). The f u value of the compounds in the CSF, calculated on the basis of their f u in plasma (Fridén et al, 2010), also amounted to 1. As a consequence, the total concentrations of TREO and S,S-EBDM determined in the plasma, brain tissue, and CSF of the rats that received TREO, exactly reflected the free drug concentration.…”

“…Levels of the analytes in the brain tissue were calculated knowing that 1 mM in the brain homogenate supernatant was equivalent to 6 mmol/kg in the brain tissue. The total concentrations in brain tissue were corrected for the analytes present in residual brain blood using the method described by Fridén et al (2010):…”

“…Concentrations of unbound TREO, S,S-EBDM, and S,S-DEB in plasma, brain tissue, and CSF were calculated as a product of the total concentration and the unbound fraction factor (f u ). The value of f u for CSF was calculated using the following formula (Fridén et al, 2010):…”

An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

“…For all studies, no brain perfusion occurred before brain tissue extraction for compound quantification, and no correction (Brown et al, 1986;Fridén et al, 2010) was made to the measured C b for compound in the analyzed brain tissue's capillary blood. Thus, all reported C b values include compound in brain vasculature spaces within the collected tissue.…”

Use of the Cassette-Dosing Approach to Assess Brain Penetration in Drug Discovery

“…The total brain drug concentration was corrected for the residual blood in the brain vasculature by subtracting 1.03% of the plasma concentration determined in the corresponding samples (Fridén et al, 2010). The AUC values were calculated using the trapezoid rule from 0 to 3 h.…”