Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms

Abstract

CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (Ki = 11.5 μM and Ki = 462 μM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and CYP2D4 protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain CYP2D4 mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur.

The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain

“…On the other hand, CP-101,606 diminished the CYP2D activity/protein level in the hypothalamus and striatum, and showed such a tendency in the substantia nigra after 3-week treatment. Thus, the above results show an influence of CP-101,606 on the regulation of brain CYP2D (i.e., CYP2D4, the main rat brain CYP2D enzyme), which usually proceeds at a post-transcriptional level, as indicated by previous pharmacological investigations concerning antipsychotic drugs or nicotine [ 25 , 26 , 27 , 46 ].…”

“…It seems, therefore, that differences in intracellular neurotransmitter signaling, availability of endogenous and exogenous active substances dependent on the blood–brain barrier (BBB) permeability and levels of transcription factors between neural and hepatic cells lead to differentiated expression of cytochrome P450 and its susceptibility to regulation at transcriptional or post-transcriptional level in the brain (or brain structures) and the liver. Brain CYP2Ds are usually regulated by xenobiotics at the post-transcriptional level in contrast to the liver enzyme, as shown for some psychotropic drugs and nicotine [ 3 , 25 , 26 , 27 , 28 ].…”

“…Recent studies have shown that prolonged administration of some antidepressant and neuroleptic drugs affects CYP2D activity in brain structures involved in depression and schizophrenia (respectively), and influences the therapeutic action or side effects of those drugs (reviewed by [ 3 ]). Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances in the brain, changes in their activity may modify the pharmacological action of psychotropics, as recently suggested for the investigated antidepressants (e.g., escitalopram, venlafaxine) and atypical neuroleptics (e.g., asenapine, iloperidone and lurasidone) [ 15 , 27 , 37 , 38 , 39 ]. The abovementioned three atypical neuroleptics evoked similar pattern of changes in the regional CYP2D activity in the brain, which was different from that of antidepressants, and suggested the involvement of pharmacological (receptor) mechanisms.…”

The Atypical Antipsychotic Lurasidone Affects Brain but Not Liver Cytochrome P450 2D (CYP2D) Activity. A Comparison with Other Novel Neuroleptics and Significance for Drug Treatment of Schizophrenia

“…The observation that lurasidone did not produce any changes in the expression and activity of liver CYP2D (in particular CYP2D4), while it did in the region-dependent manner in the brain (where CYP2D4 is the main CYP2D enzyme), implies that the neuroleptic exerted its effect on the brain enzyme via acting at monoaminergic receptors, and all the more so as similar effects on brain CYP2D in the frontal cortex and nigrostriatal pathway were observed for the atypical neuroleptics previously studied by us, namely, iloperidone and asenapine, which share with lurasidone similar receptor mechanisms in the brain [ 15 , 16 ]. These three atypical neuroleptics act at different types/subtypes of dopaminergic, serotonergic, or noradrenergic receptors ( Table 2 ), which are heterogeneously distributed throughout the brain in different structures and on different types of neuronal and glial cells.…”

“…Our earlier studies with other atypical drugs, asenapine and iloperidone, showed that chronic neuroleptic treatment produced drug- and brain region-dependent effects on CYP2D protein level and activity in the brain [ 15 , 16 ], some of which were common. Recent in vitro results with pooled human liver microsomes and microsomes from baculovirus-infected insect cells expressing human CYPs (Supersomes) showed a low potency of lurasidone to inhibit the activity of CYP2D6 [ 17 ].…”