Inhibition and induction of CYP enzymes in humans: an update
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REVIEW ARTICLE
Inhibition and induction of CYP enzymes in humans: an update Jukka Hakkola1,2,3 · Janne Hukkanen2,4 · Miia Turpeinen1,5 · Olavi Pelkonen1 Received: 3 September 2020 / Accepted: 12 October 2020 © The Author(s) 2020
Abstract The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena. Keywords Cytochrome P450 · Inhibition · Induction · Drug–drug interaction · Herbal remedies · Environmental toxicants
Introduction Inhibition and induction of cytochrome P450 (CYP) enzymes are central mechanisms, resulting in clinically significant drug–drug interactions (DDI). Today, characteristics and regulatory factors of various CYP enzymes have been elucidated to a considerable extent (Manikandan and Nagini 2018; Zanger and Schwab 2013). Detailed mechanisms of inhibition have been uncovered by studies on isolated or expressed enzymes and tissue fractions. Nuclear receptors as important xenobiotic-sensing transcription factors and as
* Olavi Pelkonen [email protected] 1
Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, POB 5000, 90014 Oulu, Finland
2
Biocenter Oulu, University of Oulu, Oulu, Finland
3
Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
4
Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
5
Administration Center, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
regulators of CYP induction have been elucidated (Wang et al. 2012). Prediction on the basis of in vitro studies is now an integral part of early drug development (Lu and Di 2020) as well as of the medicines agency guidelines (EMA, FDA, and MHLW/PMDA). Computational models such as physiologically based pharmacokinetic models are now being used for quantitative prediction of in vivo interactions from in vitro experiments (Kato 2020; Min and Bae 2017), and these models are used extensively by drug developers before and during clinical trials. After preclinical studies,
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