Application of triple-probe microdialysis for fast pharmacokinetic/pharmacodynamic evaluation of dopamimetic activity of drug candidates in the rat brain.
The technique of microdialysis utilizing three simultaneously implanted probes in the anaesthetized rat enables monitoring of pharmacokinetic (PK) profiles of a tested drug both in blood (1st probe) and brain (2nd probe) compartments and the pharmacodynamic (PD) response of neurotransmitters (3rd probe) released into, or accumulating within the brain extracellular fluid (ECF). In the present study, the PK/PD characteristics of cocaine (psychostimulant, strong abuse potential) and methylphenidate (dopamimetic drug without reinforcing properties) and two novel NeuroSearch (NS) drug candidates, NS-A and NS-B, were examined in blood and brain microdialysates from the anaesthetized rats. The extracellular levels of dopamine (DA) were monitored in the striatum or prefrontal cortex. The NS-A compound entered the brain ECF at a slightly slower rate then methylphenidate; however, both compounds showed about the same effect on the speed of accumulation of extracellular DA concentrations, which gradually increased to about 450% of the basal, predrug levels at the end of the sampling period (180 min). The NS-B compound showed more rapid PK profiles than those observed after methylphenidate and NS-A. The concentrations of NS-B reached the maximal values already 40 min after its administration, while at that time, the corresponding DA values were still unchanged. In fact, the increase in DA concentrations was about two times slower when compared to that of methylphenidate or NS-A-drugs. Faster kinetics of NS-B and its delayed effect on extracellular DA suggests that this compound is metabolized to an active intermediate product, which itself exerts stronger dopamimetic activity in the rat prefrontal cortex that the original NS-B substance. The present study illustrates the feasibility of triple-probe microdialysis to monitor the rate of extracellular accumulation of a drug candidate and DA levels in vivo and compare the resulting PK/PD profiles to those obtained for cocaine and methylphenidate. These measures may serve as initial neurochemical indicators of potential psychomimetic or reinforcing properties of the tested substances.
Weikop
Pia
P
Department of Microdialysis, NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark. piw@neurosearch.dk
Egestad
Börje
B
Kehr
Jan
J
D000818:Animals; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000097:blood / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008774:Methylphenidate / Q000097:blood / Q000493:pharmacokinetics; D017551:Microdialysis / Q000295:instrumentation / Q000379:methods*; D008839:Microelectrodes / Q000592:standards; D009448:Neurochemistry / Q000295:instrumentation / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018491:Dopamine Agonists; D008774:Methylphenidate; D003042:Cocaine; D004298:Dopamine