An integrated microdialysis rat model for multiple pharmacokinetic/pharmacodynamic investigations of serotonergic agents.
BACKGROUND
Integrated in vivo models applying intracerebral microdialysis in conjunction with automated serial blood sampling in conscious, freely moving rodents are an attractive approach for pharmacokinetic (PK) and simultaneous pharmacokinetic/pharmacodynamic (PK/PD) investigations of CNS active drugs within the same animal. In this work, the ability to obtain and correlate data in this manner was evaluated for the selective serotonin (5-HT) reuptake inhibitor (SSRI) escitalopram.


METHODS
An instrumented rat model equipped with an intracerebral hippocampal microdialysis probe and indwelling arterial and venous catheters was applied in the studies. Concomitant with brain microdialysis, serial blood sampling was conducted by means of an automated blood sampling device. The feasibility of the rat model for simultaneous PK/PD investigations was examined by monitoring plasma and brain extracellular concentrations of escitalopram along with SSRI-associated pharmacological activity, monitored as changes in brain 5-HT levels and plasma corticosterone levels.


RESULTS
Combining intracerebral microdialysis and automated blood sampling did not cause any detectable physiological changes with respect to basal levels of plasma corticosterone or brain 5-HT levels. Furthermore, the PK of escitalopram in hippocampus following intravenous injection was not influenced by the presence of vascular catheters. Conversion of escitalopram dialysate concentrations into absolute extracellular levels by means of in vivo retrodialysis was verified by the no-net-flux method, which gave similar recovery estimates. The PK of escitalopram could be characterized simultaneously in plasma and the hippocampus of conscious, freely moving rats. Concomitantly, the modulatory and functional effects of escitalopram could be monitored as increases in brain 5-HT and plasma corticosterone levels following drug administration.


CONCLUSIONS
The applicability of intracerebral microdialysis combined with arterial blood sampling was demonstrated for simultaneous PK/PD investigations of escitalopram in individual rats under non-stressful conditions. Together, these temporal relationships provide multiple PK/PD information in individual animals, hence minimizing inter-animal variation using a reduced number of animals.
Bundgaard
Christoffer
C
Discovery ADME, H. Lundbeck A/S, Copenhagen, Denmark. cbun@lundbeck.com
Jørgensen
Martin
M
Mørk
Arne
A
D000818:Animals; D001923:Brain Chemistry; D002408:Catheters, Indwelling; D015283:Citalopram / Q000032:analysis / Q000493:pharmacokinetics*; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D008297:Male; D017551:Microdialysis / Q000379:methods*; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000032:analysis / Q000493:pharmacokinetics*
D015283:Citalopram; D003345:Corticosterone; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors