TY - JOUR T1 - Impact of P-glycoprotein-mediated active efflux on drug distribution into lumbar cerebrospinal fluid in nonhuman primates JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000099 SP - DMD-AR-2020-000099 AU - Yoko Nagaya AU - Kazuhide Katayama AU - Hiroyuki Kusuhara AU - Yoshitane Nozaki Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/08/29/dmd.120.000099.abstract N2 - Estimation of unbound drug concentration in the brain (Cu,brain) is an essential part of central nervous system (CNS) drug development. As a surrogate for Cu,brain in humans and nonhuman primates, drug concentration in the cerebrospinal fluid (CCSF) collected by lumbar puncture is often used; however, the predictability of Cu,brain by lumbar CCSF is unclear, particularly for substrates of the active efflux transporter P-glycoprotein (P-gp). Here, we measured lumbar CCSF in cynomolgus monkey after single intravenous administration of 10 test compounds with varying P-gp transport activities. The in vivo lumbar CSF-to-plasma unbound drug concentration ratios (Kp,uu,lumbar CSF) of nonsubstrates or weak substrates of P-gp were in the range 0.885-1.34, whereas those of good substrates of P-gp were in the range 0.195-0.458, and were strongly negatively correlated with in vitro P-gp transport activity. Moreover, concomitant treatment with a P-gp inhibitor, zosuquidar, increased the Kp,uu,lumbar CSF values of the good P-gp substrates, indicating that P-gp-mediated active efflux contributed to the low Kp,uu,lumbar CSF values of these compounds. Compared with the drug concentrations in the cisternal CSF and interstitial fluid (ISF) that we previously determined in cynomolgus monkeys, the lumbar CCSF were more than triple for 2 and all of the good P-gp substrates examined, respectively. Although lumbar CCSF may overestimate cisternal CSF and ISF concentrations of good P-gp substrates, lumbar CCSF allowed discrimination of good P-gp substrates from the weak and nonsubstrates and can be used to estimate the impact of P-gp-mediated active efflux on drug CNS penetration. Significance Statement This is the first study to systematically evaluate the penetration of various P-gp substrates into lumbar CSF in nonhuman primates. Lumbar CSF may contain >3-fold higher concentrations of good P-gp substrates than ISF and cisternal CSF, but was able to discriminate the good substrates from the weak or nonsubstrates. Because lumbar CSF is more accessible than ISF and cisternal CSF in nonhuman primates, these findings will help increase our understanding of drug CNS penetration at the nonclinical stage. ER -