Abstract
Background: Available in-vitro and animal studies indicate that inflammation impacts cytochromes P450 (CYP) activity via multiple and complex transcriptional and post-transcriptional mechanisms, depending on the specific CYP isoforms and the nature of inflammation mediators. It is essential to review the current published data on the impact of inflammation on CYP activities in adults to support drug individualization based on comorbidities and diseases in clinical practice. Methods: This systematic review was conducted in PubMed through 7th January 2021 looking for articles that investigated the consequences of inflammation on CYP activities in adults. Information on the source of inflammation, victim drugs (and CYPs involved), effect of disease-drug interaction, number of subjects, and study design were extracted. Results: The search strategy identified 218 studies and case reports that met our inclusion criteria. These articles were divided into fourteen different sources of inflammation (such as infection, autoimmune diseases, cancer, therapies with immunomodulator…). The impact of inflammation on CYP activities appeared to be isoform-specific and dependent on the nature and severity of the underlying disease causing the inflammation. Some of these drug-disease interactions had a significant influence on drug pharmacokinetic parameters and on clinical management. For example, clozapine levels doubled with signs of toxicity during infections and the concentration ratio between clopidogrel’s active metabolite and clopidogrel is 48-fold lower in critically ill patients. Infection and CYP3A were the most cited perpetrator of inflammation and the most studied CYP, respectively. Moreover, some data suggest that resolution of inflammation results in a return to baseline CYP activities. Conclusion: Convincing evidence shows that inflammation is a major factor to be taken into account in drug development and in clinical practice to avoid any efficacy or safety issues because inflammation modulates CYP activities and thus drug pharmacokinetics. The impact is different depending on the CYP isoform and the inflammatory disease considered. Moreover, resolution of inflammation appears to result in a normalization of CYP activity. However, some results are still equivocal and further investigations are thus needed.
Highlights
Cytochromes P450 (CYP) are the major drug-metabolizing enzymes (DME) responsible for 75% of drug metabolism, making them decisive in the efficacy and safety of drugs (Wienkers and Heath, 2005)
The drug-disease interactions found in the selected articles were divided into fourteen different sources of inflammation: unspecified source of inflammation (Table 1), infection (Table 2A), infection-example hepatitis (Table 2B), infectionexample HIV (Table 3C), infection-example SARS-CoV-2 (Table 2D), vaccination (Table 3), kidney disease (Table 4), liver disease (Table 5), lung disease (Table 6), heart disease (Table 7), critically ill patients (Table 8), diabetes (Table 9), autoimmune diseases (Table 10), surgery (Table 11), cancer (Table 12), therapies with immunomodulator (Table 13) and therapies with anti-TNF-α and -mabs (Table 14)
CYP3A subfamilies refers to CYP3A4 and Inflammation characterized by Victim drugs (CYPs concerned)
Summary
Cytochromes P450 (CYP) are the major drug-metabolizing enzymes (DME) responsible for 75% of drug metabolism, making them decisive in the efficacy and safety of drugs (Wienkers and Heath, 2005). Inflammation is a response to endogenous or exogenous aggression that can be acute or chronic It is prominent in many diseases, such as infection, trauma, surgery, arthritis, asthma, atherosclerosis, autoimmune disease, various immunologically mediated and crystal-induced inflammatory conditions, diabetes and cancer, to name a few (Gabay and Kushner, 1999; Germolec et al, 2018; Stavropoulou et al, 2018). This universal protective response involves innate and adaptative immunity and is present in virtually all tissues. It is essential to review the current published data on the impact of inflammation on CYP activities in adults to support drug individualization based on comorbidities and diseases in clinical practice
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