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


CONCLUSIONS
This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.
Van Calsteren
K
K
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium.
Verbesselt
R
R
Beijnen
J
J
Devlieger
R
R
De Catte
L
L
Chai
D C
DC
Van Bree
R
R
Heyns
L
L
de Hoon
J
J
Amant
F
F
D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics*; D001761:Bleomycin / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D003606:Dacarbazine / Q000097:blood / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics; D015251:Epirubicin / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics; D013058:Mass Spectrometry; D010215:Papio; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000378:metabolism*; D014747:Vinblastine / Q000097:blood / Q000493:pharmacokinetics
D001761:Bleomycin; C012358:4-hydroxycyclophosphamide; D015251:Epirubicin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil