Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters

• Published in: Journal of pharmaceutical sciences Vol. 106; no. 9; pp. 2345 - 2356
• Main Authors: Yahata, Masahiro, Chiba, Koji, Watanabe, Takao, Sugiyama, Yuichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2017
• Subjects: Animals; Biological Transport - physiology; blood-brain barrier; Blood-Brain Barrier - metabolism; Brain - metabolism; central nervous system; Humans; P-glycoprotein; passive diffusion/transport; PET; Pharmaceutical Preparations - blood; Pharmaceutical Preparations - metabolism; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins - metabolism; passive diffusion/transport; SER; BBB; SSRIs; Kp,uu,brain; PAX; OATP1A2; Css,u; Cu,brain; MLN; SPECT; FLV; BPbaseline; Ru/Ki; ESC; in vitro Ki,parent; Ctotal,plasma; Cu,plasma,parent; NFL; SNRIs; BPdrug; DUL; Ki,u,plasma; FUL; blood-brain barrier; BCRP; Ru/Ki,parent; hCMEC/D3; P-gp; Ru/Ki,met; Ki,total,plasma; Kp,brain; central nervous system; CIT; P-glycoprotein; SERT; PET; VEN; Cu,plasma
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2017.05.007

Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro Ki values for human SERT and plasma concentrations of unbound drug (Cu,plasma), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro Ki values were compared with the means of in vivo Ki values (Ki,u,plasma) which were calculated as Cu,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro Ki values for 7 drugs were comparable to their in vivo Ki,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro Ki values and Cu,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments.