Investigation of the CNS penetration of a potent 5-HT2a receptor antagonist (MDL 100,907) and an active metabolite (MDL 105,725) using in vivo microdialysis sampling in the rat.

MDL 100,907 is a selective 5-HT2a receptor antagonist which is currently being developed for the treatment of schizophrenia. Pharmacokinetic studies of MDL 100,907 in rats and dogs show that the drug is well absorbed but undergoes extensive first-pass metabolism to an active metabolite (MDL 105,725). The purpose of this study was to determine concentrations of MDL 100,907 and MDL 105,725 in the brain extracellular fluid (ECF) after administration of MDL 100,907. In vivo microdialysis sampling was used to determine the brain penetration of both parent (MDL 100,907) and metabolite (MDL 105,725). Animals (n = 3/dose) were given 5 i.v. and 50 mg kg-1 oral doses of MDL 100,907. Brain medial prefrontal cortex (mPFC) ECF concentrations were determined using microdialysis and plasma levels were determined by collecting blood samples through an indwelling cannula implanted in the jugular vein. Dialysate samples were analyzed using an LC/MS/MS assay. The data presented in this report show that the blood brain barrier (BBB) permeability of MDL 100,907 is more than four times (4x) that of MDL 105,725 and that MDL 100,907 does not undergo significant metabolism to MDL 105,725 in the brain. It appears, from the data presented, that MDL 100,907 is the predominant active species present in the brain at high doses.