In vitro P-glycoprotein efflux inhibition by atypical antipsychotics is in vivo nicely reflected by pharmacodynamic but less by pharmacokinetic changes |
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Authors: | Schmitt Ulrich Kirschbaum Katrin M Poller Birk Kusch-Poddar Manisha Drewe Jürgen Hiemke Christoph Gutmann Heike |
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Institution: | a Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes-Gutenberg University Mainz, D-55131 Mainz, Germanyb Division of Clinical Pharmacology and Toxicology, University Hospital Basel, CH-4031 Basel, Switzerland |
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Abstract: | BackgroundP-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.MethodsWe 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.ResultsIn 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.ConclusionsCombination 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. |
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Keywords: | Blood-brain barrier P-glycoprotein Pharmacokinetics Pharmacodynamics Mice Antipsychotics |
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