The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

Przemysław J Danek,Władysława A Daniel,Jacek Wójcikowski

doi:10.1007/s43440-020-00102-5

Przemysław J Danek, Władysława A Daniel + Show 1 more

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https://doi.org/10.1007/s43440-020-00102-5

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Abstract

BackgroundThe present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes).MethodsThe activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC.ResultsIloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (Ki = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (Ki = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (Ki = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (Ki = 37.5 and 85 µM in microsomes and supersomes).ConclusionThe examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.

Highlights

The cytochromes P450 (CYPs) constitute the major family of enzymes capable of catalyzing the oxidative biotransformation of most drugs and other lipophilic xenobiotics, they are of particular relevance to clinical pharmacology [1]
To investigate whether iloperidone and lurasidone affect the activity of cytochrome P450 (CYP) enzymes, the probe reaction assays were conducted with varied concentration of the neuroleptics
Iloperidone attenuated the activity of CYP2C19 (Ki = 6.5 and 32 μM in liver microsomes and supersomes, respectively) and CYP1A2 (Ki = 45 and 31 μM in liver microsomes and supersomes, respectively)

Summary

Introduction

The cytochromes P450 (CYPs) constitute the major family of enzymes capable of catalyzing the oxidative biotransformation of most drugs and other lipophilic xenobiotics, they are of particular relevance to clinical pharmacology [1]. Iloperidone, a piperidinyl benzisoxazole derivative, is an atypical neuroleptic drug approved for the treatment of acute schizophrenia in adult patients [4]. It produces an antagonistic effect by a high-affinity binding to serotonin 5-HT2A, and dopamine D2 and D3 receptors, moderate affinity binding to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine α1 receptors, and low-affinity binding to serotonin 5-HT1A, dopamine D1, and histamine H 1 receptors. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 μM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 μM in microsomes and supersomes). The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy

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