Ira Kantrowitz-Gordon1, Karen Hays2, Olumide Kayode3,4, Aditya R Kumar2, Henry G Kaplan5, Joel M Reid4, Stephanie L Safgren4, Matthew M Ames4, Thomas R Easterling2,6, Mary F Hebert7,8. 1. Department of Family and Child Nursing, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. 2. Department of Pharmacy, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. 3. Center for Cancer Research, National Cancer Institute, 8560 Progress Drive, Fredrick, MD, 21702, USA. 4. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, 200 First St SW, Rochester, MN, 55905, USA. 5. Swedish Cancer Institute, Swedish Medical Center, 1221 Madison St #500, Seattle, WA, 98104, USA. 6. Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. 7. Department of Pharmacy, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. mhebert@u.washington.edu. 8. Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. mhebert@u.washington.edu.
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.
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.
Authors: Aida Kulo; Mariska Y Peeters; Karel Allegaert; Anne Smits; Jan de Hoon; Rene Verbesselt; Liesbeth Lewi; Marc van de Velde; Catherijne A J Knibbe Journal: Br J Clin Pharmacol Date: 2013-03 Impact factor: 4.335
Authors: Rachel J Ryu; Sara Eyal; Henry G Kaplan; Arezoo Akbarzadeh; Karen Hays; Kristin Puhl; Thomas R Easterling; Stacey L Berg; Kathleen A Scorsone; Eric M Feldman; Jason G Umans; Menachem Miodovnik; Mary F Hebert Journal: Cancer Chemother Pharmacol Date: 2014-02-15 Impact factor: 3.333
Authors: Richard T Hoppe; Ranjana H Advani; Weiyun Z Ai; Richard F Ambinder; Patricia Aoun; Celeste M Bello; Philip J Bierman; Kristie A Blum; Robert Chen; Bouthaina Dabaja; Ysabel Duron; Andres Forero; Leo I Gordon; Francisco J Hernandez-Ilizaliturri; Ephraim P Hochberg; David G Maloney; David Mansur; Peter M Mauch; Monika Metzger; Joseph O Moore; David Morgan; Craig H Moskowitz; Matthew Poppe; Barbara Pro; Jane N Winter; Joachim Yahalom; Hema Sundar Journal: J Natl Compr Canc Netw Date: 2012-05 Impact factor: 11.908