Pharmacokinetic modelling of blood-brain barrier transport of escitalopram in rats.
This study examined the pharmacokinetics and distribution of escitalopram in the brain extracellular fluid in rats by the concurrent use of intracerebral microdialysis and serial blood sampling. Following three constant intravenous infusions, drug concentrations in the hippocampus and plasma were monitored for 6 h. To estimate the integrated pharmacokinetics and intercompartmental transport parameters, including blood-brain barrier (BBB) transport over the entire dose range, unbound brain and plasma escitalopram concentration data from all doses were simultaneously analysed using compartmental modelling. The pharmacokinetic analysis revealed that systemic clearance decreased as a function of dose, which was incorporated in the integrated model. Escitalopram was rapidly and extensively transported across the BBB and distributed into the brain extracellular fluid. The modelling resulted in an estimated influx clearance into the brain of 535 microl/min/g brain, resulting in an unbound brain-to-plasma AUC ratio of 0.8 independent of escitalopram dose. The model may be applied for preclinical evaluations or predictions of escitalopram concentration-time courses in plasma as well as at the target site in the CNS for various dosing scenarios. In addition, this modelling approach may also be valuable for studying BBB transport characteristics for other psychotropic agents.
Bundgaard
Christoffer
C
Discovery ADME, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark. cbun@lundbeck.com
Jørgensen
Martin
M
Larsen
Frank
F
D000818:Animals; D001812:Blood-Brain Barrier; D015283:Citalopram / Q000493:pharmacokinetics*; D045604:Extracellular Fluid / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
D015283:Citalopram