ArticleDrug metabolism and disposition: the biological fate of chemicals2012
Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 55 citations in OpenAlex.
- Association of Antiepileptic Medications with Outcomes after Allogeneic Hematopoietic Cell Transplantation with Busulfan/Cyclophosphamide Conditioning.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation · 2019Trial
- Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition.Clinical pharmacology and therapeutics · 2019Trial
- Cytochrome P450 2B6*5 Increases Relapse after Cyclophosphamide-Containing Conditioning and Autologous Transplantation for Lymphoma.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation · 2015Trial
- A pilot pharmacologic biomarker study in HLA-haploidentical hematopoietic cell transplant recipients.Cancer chemotherapy and pharmacology · 2013Trial
- Mechanisms underlying seizures and hypothermia during busulphan administration.Bone marrow transplantation · 2025Article
- Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with 4hydroxycyclophosphamide formation in children with Cancer.Cancer chemotherapy and pharmacology · 2024Article
- Parthenolide enhances the metronomic chemotherapy effect of cyclophosphamide in lung cancer by inhibiting the NF-kB signaling pathway.World journal of clinical oncology · 2024Article
- Cyclophosphamide Pharmacogenomic Variation in Cancer Treatment and Its Effect on Bioactivation and Pharmacokinetics.Advances in pharmacological and pharmaceutical sciences · 2024Review
- Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma.Scientific reports · 2023Article
- Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition.British journal of clinical pharmacology · 2022Article
- CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function.Scientific reports · 2022Article
- Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group.Pediatric blood & cancer · 2021Article
- Pharmacokinetics and Pharmacogenetics of Cyclophosphamide in a Neonate and Infant Childhood Cancer Patient Population.Pharmaceuticals (Basel, Switzerland) · 2021Article
- CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations-Implication for Drug Safety, Dosing, and Individualized Therapy.Frontiers in genetics · 2021Review
- Stereoselective Bupropion Hydroxylation by Cytochrome P450 CYP2B6 and Cytochrome P450 Oxidoreductase Genetic Variants.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Genetic Polymorphism of GSTP-1 Affects Cyclophosphamide Treatment of Autoimmune Diseases.Molecules (Basel, Switzerland) · 2020Article
- Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients.Frontiers in pharmacology · 2020Article
- The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes.British journal of clinical pharmacology · 2019Review
- Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes.Pharmacology research & perspectives · 2019Article
- Acute and fatal cardiotoxicity following high-dose cyclophosphamide in a patient undergoing autologous stem cell transplantation for systemic sclerosis despite satisfactory cardiopulmonary screening.Bone marrow transplantation · 2017Article
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9 authors at 3 institutions in 1 country.
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Abstract
Results from retrospective studies on the relationship between cytochrome P450 (P450) 2B6 (CYP2B6) genotype and cyclophosphamide (CY) efficacy and toxicity in adult cancer patients have been conflicting. We evaluated this relationship in children, who have faster CY clearance and receive different CY-based regimens than adults. These factors may influence the P450s metabolizing CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Therefore, we sought to characterize the in vitro and in vivo roles of hepatic CYP2B6 and its main allelic variants in 4HCY formation. CYP2B6 is the major isozyme responsible for 4HCY formation in recombinant P450 Supersomes. In human liver microsomes (HLM), 4HCY formation correlated with known phenotypic markers of CYP2B6 activity, specifically formation of (S)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolidine and hydroxybupropion. However, in HLM, CYP3A4/5 also contributes to 4HCY formation at the CY concentrations similar to plasma concentrations achieved in children (0.1 mM). 4HCY formation was not associated with CYP2B6 genotype at low (0.1 mM) or high (1 mM) CY concentrations potentially because CYP3A4/5 and other isozymes also form 4HCY. To remove this confounder, 4HCY formation was evaluated in recombinant CYP2B6 enzymes, which demonstrated that 4HCY formation was lower for CYP2B6.4 and CYP2B6.5 compared with CYP2B6.1. In vivo, CYP2B6 genotype was not directly related to CY clearance or ratio of 4HCY/CY areas under the curve in 51 children receiving CY-based regimens. Concomitant chemotherapy agents did not influence 4HCY formation in vitro. We conclude that CYP2B6 genotype is not consistently related to 4HCY formation in vitro or in vivo.
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