Factors involved in phenoconversion of CYP3A using 4β-hydroxycholesterol in stable kidney transplant recipients

Suzuki, Yosuke; Muraya, Nanako; Fujioka, Takashi; Sato, Fuminori; Tanaka, Ryota; Matsumoto, K.; Sato, Yuhki; Ohno, Keiko; Mimata, Hiromitsu; Kishino, Satoshi

doi:10.1016/j.pharep.2018.12.007

Cited by 13 publications

(21 citation statements)

References 44 publications

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“…In a prospective study of 63 stable kidney transplant recipients, CYP3A phenoconversion was studied. The CYP3A5 genotype was determined, and immunosuppressant levels were measured [ 42 ]. The authors reported that 10 CYP3A5*1 recipients had a lower CYP3A5 activity than expected based on the CYP3A5 genotype, indicating phenoconversion.…”

Section: Resultsmentioning

confidence: 99%

Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review

Klomp

Manson

Guchelaar

et al. 2020

JCM

102

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Phenoconversion is the mismatch between the individual’s genotype-based prediction of drug metabolism and the true capacity to metabolize drugs due to nongenetic factors. While the concept of phenoconversion has been described in narrative reviews, no systematic review is available. A systematic review was conducted to investigate factors contributing to phenoconversion and the impact on cytochrome P450 metabolism. Twenty-seven studies met the inclusion criteria and were incorporated in this review, of which 14 demonstrate phenoconversion for a specific genotype group. Phenoconversion into a lower metabolizer phenotype was reported for concomitant use of CYP450-inhibiting drugs, increasing age, cancer, and inflammation. Phenoconversion into a higher metabolizer phenotype was reported for concomitant use of CYP450 inducers and smoking. Moreover, alcohol, pregnancy, and vitamin D exposure are factors where study data suggested phenoconversion. The studies reported genotype–phenotype discrepancies, but the impact of phenoconversion on the effectiveness and toxicity in the clinical setting remains unclear. In conclusion, phenoconversion is caused by both extrinsic factors and patient- and disease-related factors. The mechanism(s) behind and the extent to which CYP450 metabolism is affected remain unexplored. If studied more comprehensively, accounting for phenoconversion may help to improve our ability to predict the individual CYP450 metabolism and personalize drug treatment.

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Section: Resultsmentioning

confidence: 99%

Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review

Klomp

Manson

Guchelaar

et al. 2020

JCM

102

View full text Add to dashboard Cite

show abstract

“…Prediction of DDI however could be hampered, since COVID-19 patients may experience phenoconversion whereby some genotypic extensive metabolizers transiently exhibit a decline in drug metabolizing enzyme activities comparable to that of poor metabolizers because of cytokine storm [ 43 , 44 ]. The problem of phenoconversion due to hyperactive immune system may increase the cardiac related side effects of drugs used in the course of COVID-19 (e.g.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions

Awortwe

Cascorbi

2020

Pharmacological Research

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“…Furthermore, COVID-19 patients may exhibit features of systemic hyperinflammation (designated as "cytokine storm"), which can be associated with socalled "phenoconversion," a phenomenon whereby extensive metabolizers transiently exhibit drug metabolizing enzyme activity at a comparable level as that of poor metabolizers. 6,7 Commonly, ISDs are characterized by a narrow therapeutic index and wide PK variability, requiring close monitoring of the blood concentrations. Also, the metabolic pathways involved in clearance of ISDs make these drugs extremely susceptible for drug-drug interactions (DDIs).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions

Elens

Langman

Hesselink

et al. 2020

Therapeutic Drug Monitoring

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Background: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. Methods: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. Results: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. Conclusions: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.

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Factors involved in phenoconversion of CYP3A using 4β-hydroxycholesterol in stable kidney transplant recipients

Cited by 13 publications

References 44 publications

Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review

Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review

Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions

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