Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies

El-Serafi, Ibrahim; Fares, Mohammad M.; Abedi‐Valugerdi, Manuchehr; Afsharian, Parvaneh; Moshfegh, Ali; Terelius, Ylva; Potácová, Zuzana; Hassan, Manal M.

doi:10.1038/tpj.2014.82

Cited by 23 publications

(20 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the effect was not evident in POR*28 carriers. A previous study demonstrated a significant correlation between CPA clearance and POR/CYP ratio (El-Serafi et al, 2015b), which might signify the importance of the level of expression of the gene in CPA metabolism and clearance.…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients

et al. 2020

View full text Add to dashboard Cite

Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (V D) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m 2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average V D compared to patients who received 600 mg/m 2. A 0.1 m 2 unit increase in body surface area (BSA) was associated with a 5.6% increment in V D. The mean V D (33.5 L) in underweight group (BMI < 18.5 kg/m 2) was significantly lower compared to those of overweight (48.1 L) or

show abstract

Section: Discussionmentioning

confidence: 86%

“…The plasma concentrations of CPA was determined as described previously with some modifications (El-Serafi et al, 2015b). To each 250 μl of thawed plasma samples, 25 ml of internal standard (ifosfamide, 20 mM, Vnr079111, Denmark), and 1.25 ml ethyl acetate were added.…”

Section: Determination Of Plasma Cyclophosphamide Concentrationsmentioning

confidence: 99%

Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Cyclophosphamide undergoes hepatic hydroxylation to form 4‐hydroxycyclophosphamide (4‐OHCP), which represents the major route of metabolism of the drug and accounts for 70–80% of the dose . This route can be catalysed by any a number of cytochrome P450 (CYP) enzymes including CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 and CYP2J2 . CYP2B6 and CYP2C19 are the enzymes with the highest activity for bioactivation of cyclophosphamide.…”

Section: Introductionmentioning

confidence: 99%

“…6 This route can be catalysed by any a number of cytochrome P450 (CYP) enzymes including CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 and CYP2J2. [8][9][10][11][12][13][14][15][16] CYP2B6 and CYP2C19 are the enzymes with the highest activity for bioactivation of cyclophosphamide.…”

Section: Introductionmentioning

confidence: 99%

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

Helsby

Yong

Kan

et al. 2019

Brit J Clinical Pharma

View full text Add to dashboard Cite

Cyclophosphamide is an alkylating agent used in the treatment of solid and haematological malignancies and as an immunosuppressive agent. As a prodrug, it is dependent on bioactivation to the active phosphoramide mustard metabolite to elicit its therapeutic effect. This focused review will highlight the evidence for the role of germline pharmacogenetic variation in both plasma pharmacokinetics and clinical outcomes. There is a substantial indication from 13 pharmacokinetic and 17 therapeutic outcome studies, in contexts as diverse as haematological malignancy, breast cancer, systemic lupus erythematosus and myeloablation, that pharmacogenetic variation in both CYP2C19 and CYP2B6 influence the bioactivation of cyclophosphamide. An additional role for pharmacogenetic variation in ALDH1A1 has also been reported. Future studies should comprehensively assess these 3 pharmacogenes and undertake appropriate statistical analysis of gene–gene interactions to confirm these findings and may allow personalised treatment regimens.

show abstract

“…CYP2J2 is also expressed in a wide variety of tumours and tumour cell lines, where it appears to promote cell survival [6].…”

Section: Introductionmentioning

confidence: 99%

Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2

et al. 2016

View full text Add to dashboard Cite

Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies

Cited by 23 publications

References 40 publications

Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients

Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2

Contact Info

Product

Resources

About