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1. Pharmacol Biochem Behav. 2012 Apr 15. [Epub ahead of print]

In vitro P-glycoprotein efflux inhibition by atypical antipsychotics is in vivo
nicely reflected by pharmacodynamic but less by pharmacokinetic changes.

Schmitt U, Kirschbaum KM, Poller B, Kusch-Poddar M, Drewe J, Hiemke C, Gutmann H.

Department of Psychiatry and Psychotherapy, University Medical Center of the
Johannes-Gutenberg University Mainz, D-55131 Mainz, Germany.

BACKGROUND: P-glycoprotein (P-gp), an efflux transporter of the blood-brain
barrier, limits the access of multiple xenobiotics to the central nervous system
(CNS). Thus drug-dependent inhibition, induction or genetic variation of P-gp
impacts drug therapy. METHODS: We investigated atypical antipsychotics and their
interaction with P-gp. Amisulpride, clozapine, N-desmethylclozapine, olanzapine,
and quetiapine were assessed in vitro on their inhibitory potential and in vivo
on their disposition in mouse serum and brain, and behaviourally on the RotaRod
test. In vivo wildtype (WT) and mdr1a/1b double knockout mice (mdr1a/1b (-/-,
-/-); KO) were investigated. RESULTS: In rhodamine 123 efflux assay drugs
inhibitory potency to P-gp could be ranked
quetiapine>N-desmethylclozapine>clozapine>olanzapine. When treating WT and KO
mice i.p. and assessing brain and serum levels by HPLC analysis, P-gp expression
has the highest but a rather short effect on the distribution of amisulpride,
whereas the others ranked N-desmethylclozapine>olanzapine>quetiapine>clozapine;
contrasted by in vivo behavioral changes at various time points. Here
quetiapine>clozapine>olanzapine impacts behavior most when P-gp is lacking.
Present results indicate the relevance of P-gp expression for CNS-drug therapy.
CONCLUSIONS: Combination of in vitro, and in vivo methods highlights that
inhibitory potency did not reflect P-gp related drug disposition. But, when drugs
were ranked for inhibitory potency, this order is reflected in pharmacodynamic
changes or vice versa. Pharmacodynamic effects otherwise were at most correlated
to drug brain levels, which however, were present only to a limited extent (by
positron emission tomography) accessible in humans.

Copyright © 2012. Published by Elsevier Inc.

PMID: 22525746 [PubMed - as supplied by publisher]