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In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug-drug interactions.

ABSTRACT: It is widely accepted that today's practice of polypharmacy inevitably increases the incidence of drug-drug interactions (DDIs). Serious DDI is a major liability for any new chemical entity (NCE) entering the pharmaceutical market. As such, pharmaceutical companies employ various strategies to avoid problematic compounds for clinical development. A key cause for DDIs is the inhibition of cytochrome P450 enzymes (CYPs) that are responsible for metabolic clearance of many drugs. Screening for inhibition potency of CYPs by NCEs has therefore become a routine practice during the drug discovery stage. However, in order to make proper use of DDI data, an understanding of the strengths and weaknesses of the various experimental systems in current use is required. An illustrated review of experimental practices is presented with discussion of likely future developments. The combination of high quality in vitro data generation and the application of in vivo CYP inhibition modelling approaches should allow more informed decisions to be made in the search for drug molecules with acceptable DDI characteristics.

SUBMITTER: Fowler S

PROVIDER: S-EPMC2751392 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug-drug interactions.

Fowler Stephen S Zhang Hongjian H

The AAPS journal 20080601 2

It is widely accepted that today's practice of polypharmacy inevitably increases the incidence of drug-drug interactions (DDIs). Serious DDI is a major liability for any new chemical entity (NCE) entering the pharmaceutical market. As such, pharmaceutical companies employ various strategies to avoid problematic compounds for clinical development. A key cause for DDIs is the inhibition of cytochrome P450 enzymes (CYPs) that are responsible for metabolic clearance of many drugs. Screening for inhi ...[more]

PMID: 18686042

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Project description:The major human liver drug metabolising cytochrome P450 (CYP) enzymes are downregulated during inflammation and infectious disease state, especially during coronavirus disease 2019 (COVID-19) infection. The influx of proinflammatory cytokines, known as a 'cytokine storm', during severe COVID-19 leads to the downregulation of CYPs and triggers new cytokine release, which further dampens CYP expression. Impaired drug metabolism, along with the inevitable co-administration of drugs or 'combination therapy' in patients with COVID-19 with various comorbidities, could cause drug-drug interactions, thus worsening the disease condition. Genetic variability or polymorphism in CYP2C9 across different ethnicities could contribute to COVID-19 susceptibility. A number of drugs used in patients with COVID-19 are inducers or inhibitors of, or are metabolised by, CYP2C9, and co-administration might cause pharmacokinetic and pharmacodynamic interactions. It is also worth mentioning that some of the COVID-19 drug interactions are due to altered activity of other CYPs including CYP3A4. Isoniazid/rifampin for COVID-19 and tuberculosis co-infection; lopinavir/ritonavir and cobicistat/remdesivir combination therapy; or multi-drug therapy including ivermectin, azithromycin, montelukast and acetylsalicylic acid, known as TNR4 therapy, all improved recovery in patients with COVID-19. However, a combination of CYP2C9 inducers, inhibitors or both, and plausibly different CYP isoforms could lead to treatment failure, hepatotoxicity or serious side effects including thromboembolism or bleeding, as observed in the combined use of azithromycin/warfarin. Further, herbs that are CYP2C9 inducers and inhibitors, showed anti-COVID-19 properties, and in silico predictions postulated that phytochemical compounds could inhibit SARS-CoV-2 virus particles. COVID-19 vaccines elicit immune responses that activate cytokine release, which in turn suppresses CYP expression that could be the source of compromised CYP2C9 drug metabolism and the subsequent drug-drug interaction. Future studies are recommended to determine CYP regulation in COVID-19, while recognising the involvement of CYP2C9 and possibly utilising CYP2C9 as a target gene to tackle the ever-mutating SARS-CoV-2.

Dataset Information

In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug-drug interactions.

Publications

In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug-drug interactions.

Similar Datasets

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