Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon model

Abstract

Objective The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. Methods Fluorouracil–epirubicin–cyclophosphamide (FEC) and doxorubicin–bleomycin–vinblastine–dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography–mass spectrometry (LC–MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. Results In nine baboons, at a median gestational age of 139 days (range, 93–169), FEC 100% ( n = 2), FEC 200% ( n = 1), ABVD 100% ( n = 5), and ABVD 200% ( n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 ± 3.2% ( n = 6) and 4.0 ± 1.6% ( n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 ± 7.9% and 8.7 ± 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 ± 15.5% ( n = 9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 ± 6.3% ( n = 3) and 63.0% ( n = 1) of the maternal concentrations, respectively. Conclusion This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.