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.
Highlights
Schizophrenia is a serious mental illness consisting of positive, negative, and cognitive disorders [1]
As mentioned in the introduction, in vitro studies on human liver microsomes have indicated that iloperidone has the potential to inhibit the CYP2D6 activity through direct interaction with the enzyme protein via competitive mechanism with the Ki value of 2.9 μM, which may be of pharmacological importance [30,45]
We have reported that two-week treatment with iloperidone reduces serum growth hormone (GH) level in rats [43]
Summary
Schizophrenia is a serious mental illness consisting of positive (psychotic), negative (anhedonia, emotional withdrawal), and cognitive disorders [1]. To treat this mental illness, a number of antipsychotic drugs are currently available on the market. Iloperidone is a piperidinyl-benzisoxazole derivate structurally related to risperidone, paliperidone and ziprasidone [2]. This atypical neuroleptic produces an antagonistic effect through high-affinity binding to serotonin 5-HT2A , dopamine D2 and. The receptor profile of iloperidone suggests its efficacy in alleviating the positive and negative symptoms of schizophrenia, as well as efficacy in reducing cognitive symptoms, with minimal side effects [4,5,6,7,8]. Iloperidone is extensively metabolized in the liver, by hydroxylation and carbonyl reduction (mediated by CYP2D6), and to a lesser degree O-dealkylation (mediated by CYP3A4) [9]
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