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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• 作者：Ulrich Schmitt ; Katrin M. Kirschbaum ; Birk Poller ; Manisha Kusch-Poddar ; J¨¹rgen Drewe ; Christoph Hiemke ; Heike Gutmann
• 关键词：Blood&ndash ; brain barrier ; P-glycoprotein ; Pharmacokinetics ; Pharmacodynamics ; Mice ; Antipsychotics
• 刊名：Pharmacology Biochemistry and Behavior
• 出版年：2012
• 出版时间：August, 2012
• 年：2012
• 卷：102
• 期：2
• 页码：312-320
• 全文大小：370 K

文摘

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.