Abstract
Pharmacokinetic interactions, e.g. modulation of drug transporters like P-glycoprotein at the blood-brain barrier, can be a reason for treatment non-response. This study focuses on the influence of induction of drug transporters on the disposition of the antipsychotic drugs risperidone and 9-hydroxyrisperidone. Brain and serum concentrations of risperidone and its active metabolite 9-hydroxyrisperidone, which are known P-glycoprotein substrates, were measured after drug transporter induction with rifampicin, dexamethasone or 5-pregnene-3beta-ol-20-on-16alpha-carbonitrile using high performance liquid chromatography. Disposition of risperidone and 9-hydroxyrisperidone was dramatically decreased in mouse brain and serum after drug transporter induction. The metabolism of risperidone was also affected.
Highlights
The blood-brain barrier (BBB) regulates the distribution of drugs in the central nervous system (CNS)
The results of our study revealed that all drug transporter inducer groups decreased brain distribution of risperidone and 9-hydroxyrisperidone and the risperidone active moiety of risperidone and 9-hydroxyrisperidone, PCN had the strongest effects on brain concentrations of risperidone active moiety (Figure7A-C)
By using risperidone and 9-hydroxyrisperidone concentrations as a tool we were able to evaluate the functional role of drug transporter modulation in BBB transport
Summary
The blood-brain barrier (BBB) regulates the distribution of drugs in the central nervous system (CNS). For in vivo investigations Pgp wildtype and double-knockout mice (mdr1a/1b -/-) are commercially available By using this in vivo model, the impact of P-gp on brain concentrations of different kinds of psychoactive drugs, including state of the art antipsychotics, has already been demonstrated [7,8,9]. In two animal in vivo studies risperidone and its active metabolite 9-hydroxyrisperidone, called paliperidone, showed significant changes in their disposition when wildtype mice were compared to P-gp knockout mice [7,9]. In both studies, 9-hydroxyrisperidone showed increased P-gp affinity compared to risperidone
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