caa a22 4500 477128408 CHVBK 20180405111656.0 cr unu---uuuuu 170330e19971101xx s 000 0 eng 10.1023/A:1012186519946 doi (NATIONALLICENCE)springer-10.1023/A:1012186519946 Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats [Elektronische Daten] [Takao Aoyama, Koujirou Yamamoto, Hajime Kotaki, Yasufumi Sawada, Tatsuji Iga] Purpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. Methods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. Results. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. Conclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine. Plenum Publishing Corporation, 1997 methylphenidate nationallicence rats nationallicence locomotor activity nationallicence pharmacodynamic modeling nationallicence Emax model nationallicence Aoyama Takao Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut Yamamoto Koujirou Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut Kotaki Hajime Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut Sawada Yasufumi Department of Pharmaceutics, Faculty of Pharmaceutical Science, University of Kyusyu, Maidashi, Higashi-ku, 812-82, Fukuoka, Japan aut Iga Tatsuji Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/11(1997-11-01), 1601-1606 0724-8741 14:11<1601 1997 14 11095 https://doi.org/10.1023/A:1012186519946 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012186519946 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Aoyama Takao Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Yamamoto Koujirou Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Kotaki Hajime Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 700 1- Sawada Yasufumi Department of Pharmaceutics, Faculty of Pharmaceutical Science, University of Kyusyu, Maidashi, Higashi-ku, 812-82, Fukuoka, Japan aut NATIONALLICENCE 700 1- Iga Tatsuji Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/11(1997-11-01), 1601-1606 0724-8741 14:11<1601 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer