In the development of central nervous system\n(CNS)-targeted drugs, the prediction of human CNS target\nexposure is a big challenge. Cerebrospinal fluid (CSF) concentrations\nhave often been suggested as a ââ?¬Ë?good enoughââ?¬â?¢\nsurrogate for brain extracellular fluid (brainECF, brain target\nsite) concentrations in humans. However, brain anatomy and\nphysiology indicates prudence. We have applied a multiple\nmicrodialysis probe approach in rats, for continuous measurement\nand direct comparison of quinidine kinetics in brainECF,\nCSF, and plasma. The data obtained indicated important differences\nbetween brainECF and CSF kinetics, with brainECF\nkinetics being most sensitive to P-gp inhibition. To describe the\ndata we developed a systems-based pharmacokinetic model.\nOur findings indicated that: (1) brainECF- and CSF-to-unbound\nplasma AUC0ââ?¬â??360 ratios were all over 100 %; (2) P-gp also\nrestricts brain intracellular exposure; (3) a direct transport route\nof quinidine from plasma to brain cells exists; (4) P-gp-mediated\nefflux of quinidine at the bloodââ?¬â??brain barrier seems to\nresult of combined efflux enhancement and influx hindrance;\n(5) P-gp at the bloodââ?¬â??CSF barrier either functions as an efflux\ntransporter or is not functioning at all. It is concluded that in\nparallel obtained data on unbound brainECF, CSF and plasma\nconcentrations, under dynamic conditions, is a complex but\nmost valid approach to reveal the mechanisms underlying the\nrelationship between brainECF and CSF concentrations. This\nrelationship is significantly influenced by activity of P-gp.\nTherefore, information on functionality of P-gp is required for\nthe prediction of human brain target site concentrations of P-gp\nsubstrates on the basis of human CSF concentrations.
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