Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates.

Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates. Drug Metab Pharmacokinet. 2014 Oct 25;29(5):419-26 Authors: Nagaya Y, Nozaki Y, Kobayashi K, Takenaka O, Nakatani Y, Kusano K, Yoshimura T, Kusuhara H Abstract In central nervous system drug discovery, cerebrospinal fluid (CSF) drug concentration (CCSF) has been widely used as a surrogate for unbound brain concentrations (Cu,brain). However, previous rodent studies demonstrated that when drugs undergo active efflux by transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier, the CCSF overestimates the corresponding Cu,brain. To investigate the utility of CCSF as a surrogate for interstitial fluid (ISF) concentration (CISF) in nonhuman primates, this study simultaneously determined the CCSF and CISF of 12 compounds, including P-gp substrates, under steady-state conditions in cynomolgus monkeys using intracerebral microdialysis coupled with cisternal CSF sampling. Unbound plasma concentrations of non- or weak P-gp substrates were within 2.2-fold of the CISF or CCSF, whereas typical P-gp substrates (risperidone, verapamil, desloratadine, and quinidine) showed ISF-to-plasma unbound (Kp,uu,ISF) and CSF-to-plasma unbound concentration ratios (Kp,uu,CSF) that were appreciably lower than unity. Although the Kp,uu,CSF of quinidine, verapamil, and desloratadine showed a trend of overestimating the Kp,uu,ISF, Kp,...
Source: Drug Metabolism and Pharmacokinetics - Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research