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In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug-drug interactions.
Pharmacol Rep. 2020 Jun; 72(3):612-621.PR

Abstract

BACKGROUND

Inhibition 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.

METHODS

The 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.

RESULTS

The 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.

CONCLUSION

The 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.

Authors+Show Affiliations

Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland.Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland.Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland.Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland.Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland. nfdaniel@cyf-kr.edu.pl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32219694

Citation

Wójcikowski, Jacek, et al. "In Vitro Inhibition of Human Cytochrome P450 Enzymes By the Novel Atypical Antipsychotic Drug Asenapine: a Prediction of Possible Drug-drug Interactions." Pharmacological Reports : PR, vol. 72, no. 3, 2020, pp. 612-621.
Wójcikowski J, Danek PJ, Basińska-Ziobroń A, et al. In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug-drug interactions. Pharmacol Rep. 2020;72(3):612-621.
Wójcikowski, J., Danek, P. J., Basińska-Ziobroń, A., Pukło, R., & Daniel, W. A. (2020). In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug-drug interactions. Pharmacological Reports : PR, 72(3), 612-621. https://doi.org/10.1007/s43440-020-00089-z
Wójcikowski J, et al. In Vitro Inhibition of Human Cytochrome P450 Enzymes By the Novel Atypical Antipsychotic Drug Asenapine: a Prediction of Possible Drug-drug Interactions. Pharmacol Rep. 2020;72(3):612-621. PubMed PMID: 32219694.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug-drug interactions. AU - Wójcikowski,Jacek, AU - Danek,Przemysław J, AU - Basińska-Ziobroń,Agnieszka, AU - Pukło,Renata, AU - Daniel,Władysława A, Y1 - 2020/03/26/ PY - 2019/11/19/received PY - 2020/02/26/accepted PY - 2020/02/20/revised PY - 2020/3/29/pubmed PY - 2020/3/29/medline PY - 2020/3/29/entrez KW - Asenapine KW - Cytochrome P450 KW - Human liver microsomes KW - Inhibition KW - cDNA-expressed CYP enzymes SP - 612 EP - 621 JF - Pharmacological reports : PR JO - Pharmacol Rep VL - 72 IS - 3 N2 - BACKGROUND: Inhibition 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. METHODS: The 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. RESULTS: The 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. CONCLUSION: The 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. SN - 1734-1140 UR - https://www.unboundmedicine.com/medline/citation/32219694/In_vitro_inhibition_of_human_cytochrome_P450_enzymes_by_the_novel_atypical_antipsychotic_drug_asenapine:_a_prediction_of_possible_drug-drug_interactions L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32219694/ DB - PRIME DP - Unbound Medicine ER -
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