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Relationship of drug metabolizing enzyme genotype to plasma levels as well as myelotoxicity of cyclophosphamide in breast cancer patients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The cytotoxic drug cyclophosphamide (CP) is bioactivated into 4-hydroxy-cyclophosphamide (4-OH-CP) through cytochrome P450 enzymes and cleared through aldehyde dehydrogenase and glutathione S-transferase. This prospective study analyzes the influence of drug metabolizing enzyme genotype on (1) plasma 4-OH-CP:CP ratio and (2) myelotoxicity in breast cancer patients on 500 mg/m2 cyclophosphamide.

Methods

Sixty-eight female breast cancer patients on FAC (fluorouracil, adriamycin, cyclophosphamide) were included. Genotyping of cytochrome P450 enzymes CYP2B6, CYP2C9, CYP2C19, CYP3A5, aldehyde dehydrogenase (ALDH3A1), and glutathione S-transferase (GSTA1) was done either through RFLP or pyrosequencing. Plasma CP and 4-OH-CP were measured immediately and 1 and 2 h after the end of infusion through LC-MS. The leukocyte count was determined on day 10 and 20 after chemotherapy.

Results

At CP dose of 500 mg/m2, the 4-OH-CP:CP ratio was negatively affected by CYP2C19*2 genotype (p = 0.039) showing a gene-dose effect. Moreover ALDH3A1*2 genotype increased 4-OH-CP:CP ratio (p = 0.037). These effects did not remain significant in a univariate analysis of variance including all genotypes. GSTA1*B carriers were at increased risk of severe leucopenia (OR 6.94; 95% CI 1.75–27.6, p = 0.006).

Conclusion

The myelotoxicity in patients receiving FAC is related to the activity of the phase-II enzyme GSTA1 but is independent of the formation of 4-OH-CP.

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Acknowledgments

The research grant was provided by Higher Education Commission Pakistan and Ziauddin University, Karachi, Pakistan. The authors are thankful to all the administration and staff of Karachi Institute of Radiotherapy and Nuclear Medicine (KIRAN) and Jinnah Postgraduate Medical Center (JPMC), Karachi, Pakistan, as well as Dr. Rubina Ghani, Molecular and Pathological Laboratories, Karachi; Prof. N.A. Jafarey, Ziauddin University, Karachi; Dr. Sandra Lächelt, Dr. Denisa May, Jutta Finger, and Marion Pauer of the Institute of Experimental and Clinical Pharmacology, CAU, Kiel, for their support.

The study is dedicated to Dr. Muhammad Noorul Afsar [1931–1991; MBBS (Dhaka, Bangladesh), DTM&H (Liverpool, UK)] for his philanthropic general practice and life-long support of rational drug use.

Conflict of interest

It is declared that there is no conflict of interest regarding this study.

Author information

Author notes

  1. Hakimuddin Razi Ahmad

    Present address: Jinnah Medical and Dental College, Karachi, Pakistan

  2. Mike Ufer

    Present address: Novartis Institute for Biomedical Research, Basel, Switzerland

Authors and Affiliations

  1. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

    Nasir Ali Afsar

  2. Institute of Experimental and Clinical Pharmacology, Christian Albrechts University (CAU) Kiel, Hospitalstr. 4, Kiel, Germany

    Mike Ufer, Sierk Haenisch, Cornelia Remmler & Ingolf Cascorbi

  3. Karachi Institute of Radiotherapy and Nuclear Medicine, Karachi, Pakistan

    Ahmed Mateen

  4. Department of Oncology, Jinnah Postgraduate Medical Center, Karachi, Pakistan

    Ahmed Usman

  5. Ziauddin University, Clifton Campus, Shahra-e-Ghalib, Karachi, Pakistan

    Nasir Ali Afsar, Khwaja Zafar Ahmed & Hakimuddin Razi Ahmad

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  1. Nasir Ali Afsar
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Correspondence to Nasir Ali Afsar.

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Afsar, N.A., Ufer, M., Haenisch, S. et al. Relationship of drug metabolizing enzyme genotype to plasma levels as well as myelotoxicity of cyclophosphamide in breast cancer patients. Eur J Clin Pharmacol 68, 389–395 (2012). https://doi.org/10.1007/s00228-011-1134-0

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  • DOI: https://doi.org/10.1007/s00228-011-1134-0

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