In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug\u2013drug interactions

Jacek Wójcikowski,Renata Pukło,Agnieszka Basińska-Ziobroń,Władysława A Daniel,Przemysław J Danek

doi:10.1007/s43440-020-00089-z

Abstract

BackgroundInhibition of cytochrome P450 (CYP) enzymes is the most common cause of harmful drug–drug interactions. The present study aimed at examining the inhibitory effect of the novel antipsychotic drug asenapine on the main CYP enzymes in human liver.MethodsThe experiments were performed in vitro using pooled human liver microsomes and the human cDNA-expressed CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Supersomes). Activities of CYP enzymes were determined using the 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). The rates of the CYP-specific reactions were assessed in the absence and presence of asenapine using HPLC.ResultsThe obtained results showed that both in human liver microsomes and Supersomes asenapine potently and to a similar degree inhibited the activity of CYP1A2 via a mixed mechanism (Ki = 3.2 μM in liver microsomes and Supersomes) and CYP2D6 via a competitive mechanism (Ki = 1.75 and 1.89 μM in microsomes and Supersomes, respectively). Moreover, asenapine attenuated the CYP3A4 activity via a non-competitive mechanism (Ki = 31.3 and 27.3 μM in microsomes and Supersomes, respectively). In contrast, asenapine did not affect the activity of CYP2C9 or CYP2C19.ConclusionThe potent inhibition of CYP1A2 and CYP2D6 by asenapine, demonstrated in vitro, will most probably be observed also in vivo, since the calculated Ki values are close to the presumed concentration range for asenapine in the liver in vivo. Therefore, pharmacokinetic interactions involving asenapine and CYP2D6 or CYP1A2 substrates are likely to occur during their co-administration to patients.

Highlights

Cytochrome P450 (CYP) enzymes are members of a superfamily of heme-containing monooxygenases catalyzing the metabolism of endogenous substances and the majority of clinically important drugs, including psychotropics
In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug. These reactions are engaged in the first phase of xenobiotic metabolism and in the biosynthesis and metabolism of endogenous compounds
The primary goal of the firstphase metabolism of xenobiotics by cytochrome P450 is their biotransformation into an inactive form with increased solubility in water to facilitate the deactivation and excretion of xenobiotics from the body [5]

Summary

Introduction

Cytochrome P450 (CYP) enzymes are members of a superfamily of heme-containing monooxygenases catalyzing the metabolism of endogenous substances (e.g., steroids, monoaminergic neurotransmitters, and arachidonic acid) and the majority of clinically important drugs, including psychotropics. CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, constitute 13, 20−30, 4, 1.5, and 30−50% of the total CYP protein in human liver, respectively, and are involved in the metabolism of approximately 90% of all marketed drugs [1,2,3,4]. They are pivotal CYP isoforms in the evaluation of CYP-mediated drug–drug interactions. In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug. Pharmacokinetic interactions involving asenapine and CYP2D6 or CYP1A2 substrates are likely to occur during their co-administration to patients

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