PT  - JOURNAL ARTICLE
AU  - Ryosuke Shimizu
AU  - Naotaka Horiguchi
AU  - Koji Yano
AU  - Masashi Sakuramoto
AU  - Naoki Kanegawa
AU  - Shunji Shinohara
AU  - Shuichi Ohnishi
TI  - Pharmacokinetic-Pharmacodynamic Modeling of Brain Dopamine Levels Based on Dopamine Transporter Occupancy after Administration of Methylphenidate in Rats
AID  - 10.1124/jpet.118.252262
DP  - 2019 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 78--87
VI  - 369
IP  - 1
4099  - http://jpet.aspetjournals.org/content/369/1/78.short
4100  - http://jpet.aspetjournals.org/content/369/1/78.full
SO  - J Pharmacol Exp Ther2019 Apr 01; 369
AB  - Dopamine exerts various effects including movement coordination and reward. It is useful to understand the quantitative relationship between drug pharmacokinetics and target engagement such as the change in occupancy and dopamine level in brain for the proper treatment of dopamine-related diseases. This study was aimed at developing a pharmacokinetic-pharmacodynamic (PK-PD) model based on dopamine transporter (DAT) occupancies that could describe changes in extracellular dopamine levels in brain after administration of methylphenidate (a DAT inhibitor) to rat. First, uptake of fluorescent substrates was studied in DAT-expressing human embryonic kidney 293 cells and concentration dependently inhibited by methylphenidate. By analyzing the uptake of fluorescent substrates in the presence or absence of methylphenidate, a mathematical model could estimate the association and dissociation rate constants of methylphenidate for DAT. Next, we measured the concentrations of methylphenidate in plasma and cerebrospinal fluid (CSF) and extracellular dopamine levels in the nucleus accumbens after single intraperitoneal administration of methylphenidate. The concentrations of methylphenidate in plasma increased almost dose proportionally and the CSF-to-plasma concentration ratio was similar among evaluated dose. The extracellular dopamine levels also increased with dose. These data were analyzed using the mechanism-based PK-PD model, which incorporates dopamine biosynthesis, release from a synapse, reuptake via DAT into a synapse, and elimination from a synapse. Methylphenidate concentrations in plasma and dopamine profiles predicted by the PK-PD model were close to in vivo observations. In conclusion, our mechanism-based PK-PD model can accurately describe dopamine levels in the brain after administration of methylphenidate to rats.