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Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 3, pp 455–460 | Cite as

Pharmacokinetics of dacarbazine (DTIC) in pregnancy

  • Ira Kantrowitz-Gordon
  • Karen Hays
  • Olumide Kayode
  • Aditya R. Kumar
  • Henry G. Kaplan
  • Joel M. Reid
  • Stephanie L. Safgren
  • Matthew M. Ames
  • Thomas R. Easterling
  • Mary F. Hebert
Original Article

Abstract

Purpose

The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1).

Methods

Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin’s lymphoma. Drug concentrations were measured by HPLC.

Results

In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration–time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin’s lymphoma.

Conclusions

Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin’s lymphoma.

Keywords

Dacarbazine Metabolites Pharmacokinetics Pregnancy 

Notes

Acknowledgements

This work was supported in part by grant number U10HD047892 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and UL1TR000423 from the National Institutes of Health, National Center for Advancing Translational Sciences through the Clinical and Translational Science Awards Program (CTSA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

Dr. Hebert received a research grant from the Eunice Kennedy Shriver National Institute of Child Health (Grant Number U10HD047892) and the study was conducted in the University of Washington Clinical Research Unit which is supported by a grant from the National Institutes of Health, National Center for Advancing Translational Sciences through the Clinical and Translational Science Awards Program (CTSA) (Grant Number UL1TR000423).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ira Kantrowitz-Gordon
    • 1
  • Karen Hays
    • 2
  • Olumide Kayode
    • 4
    • 5
  • Aditya R. Kumar
    • 2
  • Henry G. Kaplan
    • 6
  • Joel M. Reid
    • 5
  • Stephanie L. Safgren
    • 5
  • Matthew M. Ames
    • 5
  • Thomas R. Easterling
    • 2
    • 3
  • Mary F. Hebert
    • 2
    • 3
  1. 1.Department of Family and Child NursingUniversity of WashingtonSeattleUSA
  2. 2.Department of PharmacyUniversity of WashingtonSeattleUSA
  3. 3.Department of Obstetrics and GynecologyUniversity of WashingtonSeattleUSA
  4. 4.Center for Cancer ResearchNational Cancer InstituteFredrickUSA
  5. 5.Department of Molecular Pharmacology and Experimental TherapeuticsMayo Clinic Graduate School of Biomedical SciencesRochesterUSA
  6. 6.Swedish Cancer InstituteSwedish Medical CenterSeattleUSA

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