Pharmacokinetics of dacarbazine (DTIC) in pregnancy
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).
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.
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.
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.
KeywordsDacarbazine Metabolites Pharmacokinetics Pregnancy
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).
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 was obtained from all individual participants included in the study.
- 5.Woo SY, Fuller LM, Cundiff JH, Bondy ML, Hagemeister FB, Mclaughlin P, Velasquez WS, Swan F, Alma Rodriguez M, Cabanillas F, Allen PK, Carpenter RJ (1992) Radiotherapy during pregnancy for clinical stages IA–IIA Hodgkin’s disease. Int J Radiat Oncol Biol Phys 23(2):407–412CrossRefPubMedGoogle Scholar
- 10.Fiore D, Jackson AJ, Didolkar MS, Dandu VR (1985) Simultaneous determination of dacarbazine, its photolytic degradation product, 2-azahypoxanthine, and the metabolite 5-aminoimidazole-4-carboxamide in plasma and urine by high-pressure liquid chromatography. Antimicrob Agents Chemother 27(6):977–979CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Safgren SL, Reid JM, Rios R, Ames MM (2001) Validated high-performance liquid chromatographic assay for simultaneous determination of dacarbazine and the plasma metabolites 5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide. J Chromatogr B Biomed Sci Appl 754(1):91–96CrossRefPubMedGoogle Scholar
- 15.Hoppe RT, Advani RH, Ai WZ, Ambinder RF, Aoun P, Bello CM, Bierman PJ, Blum KA, Chen R, Dabaja B, Duron Y, Forero A, Gordon LI, Hernandez-Ilizaliturri FJ, Hochberg EP, Maloney DG, Mansur D, Mauch PM, Metzger M, Moore JO, Morgan D, Moskowitz CH, Poppe M, Pro B, Winter JN, Yahalom J, Sundar H (2012) Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines. J Natl Compr Cancer Netw 10(5):589–597CrossRefGoogle Scholar
- 16.Herbst C, Rehan FA, Skoetz N, Bohlius J, Brillant C, Schulz H, Monsef I, Specht L, Engert A (2011) Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma. Cochrane Database Syst Rev 2:CD007110Google Scholar
- 25.Beal DD, Skibba JL, Whitnable KK, Bryan GT (1976) Effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide and its metabolites on Novikoff hepatoma cells. Can Res 36(8):2827–2831Google Scholar