Objective: Data on the transplacental transfer of chemotherapeutic agents are lacking. We aimed to measure the maternofetal transfer of cytotoxic drugs in a mouse model. Study design: The transplacental transfer of doxorubicin (9 mg/kg), epirubicin (11 mg/kg), vinblastine (6 mg/kg), carboplatin (50 mg/kg), paclitaxel (10 mg/kg), and cytarabine (100 mg/kg) was tested in a C57/Bl6J mouse model. Ninety minutes after intravenous (IV) drug injection on gestational day 18.5, maternal and fetal blood were collected simultaneously. Plasma drug levels were determined using high performance liquid chromatography or atomic absorption spectrometry. Results: Fetal plasma concentrations of doxorubicin, epirubicin, vinblastine, and cytarabine were 5.1% ± 0.6% (n = 8), 4.8% ± 3.8% (n = 8), 13.8% ± 5.8% (n = 6), and 56.7% ± 22.6% (n = 6) of the maternal concentrations, respectively. Total platinum passed the mouse placenta easily (117.0% ± 38.9%, n = 6). Paclitaxel could not be detected in fetal plasma samples (n = 6). Conclusions: Substantial variations in transplacental transfer were noted among the tested drugs. Current findings contribute to the understanding of reported pregnancy outcomes in humans.
StensheimHMollerBvan DijkTFossaSD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27(1):45–51.
2.
CardonickEDoughertyRGranaGGilmandyarDGhaffarSUsmaniA. Breast cancer during pregnancy: maternal and fetal outcomes. Cancer J. 2010;16(1):76–82.
3.
CardonickEIacobucciA. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004;5(5):283–291.
4.
WiebeVJSipilaPE. Pharmacology of antineoplastic agents in pregnancy. Crit Rev Oncol Hematol. 1994;16(2):75–112.
5.
Van CalsterenKHeynsLDe SmetF. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol. 2010;28(4):683–689.
6.
AmantFVan CalsterenK,. Halaska MJ, et al. Gynecologic cancers in pregnancy: guidelines of an international consensus meeting. Int J Gynecol Cancer. 2009;19(suppl 1):S1–S12.
7.
LiaoCWeiJLiQLiLLiJLiD. Efficacy and safety of cordocentesis for prenatal diagnosis. Int J Gynaecol Obstet. 2006;93(1):13–17.
8.
Von TungelnLSWilliamsLDDoergeDR. Transplacental drug transfer and frequency of Tk and Hprt lymphocyte mutants and peripheral blood micronuclei in mice treated transplacentally with zidovudine and lamivudine. Environ Mol Mutagen. 2007;48(3-4):258–269.
9.
TheilerKThe House Mouse: Atlas of Embryonic Development. New York: Springer-Verlag; 1989.
10.
SparreboomAvan TellingenONooijenWJBeijnenJH. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs. 1996;7(1):78–86.
11.
van AsperenJSchinkelAHBeijnenJHNooijenWJBorstPvan TellingenO. Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient Mice. J Natl Cancer Inst. 1996;88(14):994–999.
12.
DawrantMJGilesSBanniganJPuriP. Adriamycin produces a reproducible teratogenic model of vertebral, anal, cardiovascular, tracheal, esophageal, renal, and limb anomalies in the mouse. J Pediatr Surg. 2007;42(10):1652–1658.
13.
SchevingLESchevingLAFeuersRJTsaiTHCopeFO. Chronobiology as it relates to toxicology, pharmacology, and chemotherapy. Regul Toxicol Pharmacol. 1993;17(2 pt 1):209–218.
14.
BoughattasNALeviFFournierC. Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice. J Pharmacol Exp Ther. 1990;255(2):672–679.
15.
CollinsJM. Inter-species differences in drug properties. Chem Biol Interact. 2001;134(3):237–242.
16.
GoldsmithMASlavikMCarterSK. Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res. 1975;35(5):1354–1364.
17.
De VitaVJHellmanSRosenbergS.
Cancer Principles and Practice of Oncology. 6th ed.Philadelphia, PA: Lippincott Williams & Wilkins; 2001.
RobozJGleicherNWuKChanihianPKerenyiTHollandJ. Does doxorubicin cross the placenta?Lancet. 1979;2(8156-8157):1382–1383.
21.
D’IncalciMBrogginiMBuscagliaMPardiG. Transplacental passage of doxorubicin. Lancet. 1983;1(8314-8315):75.
22.
KarpGIvon OeyenPValoneF. Doxorubicin in pregnancy: possible transplacental passage. Cancer Treat Rep. 1983;67(9):773–777.
23.
MurrayCLReichertJAAndersonJTwiggsLB. Multimodal cancer therapy for breast cancer in the first trimester of pregnancy. A case report. JAMA. 1984;252(18):2607–2608.
24.
BarniSArdizzoiaAZanettaGStrocchiELissoniPTanciniG. Weekly doxorubicin chemotherapy for breast cancer in pregnancy. A case report. Tumori. 1992;78(5):349–350.
25.
Al-SalehENandakumaranMAl-RashdanIAl-HarmiJAl-ShammariM. Maternal-fetal transport kinetics of carboplatin in the perfused human placental lobule: in vitro study. J Matern Fetal Neonatal Med. 2007;20(9):695–701.
26.
Al-SalehEAl-HarmiJNandakumaranMAl-ShammariM. Transport kinetics of cisplatin in the perfused human placental lobule in vitro. J Matern Fetal Neonatal Med. 2008;21(10):726–731.
27.
HendersonCEEliaGGarfinkelDPoirierMCShamkhaniHRunowiczCD. Platinum chemotherapy during pregnancy for serous cystadenocarcinoma of the ovary. Gynecol Oncol. 1993;49(1):92–94.
28.
KocONMcFeeMReedEGersonSL. Detection of platinum-DNA adducts in cord blood lymphocytes following in utero platinum exposure. Eur J Cancer. 1994;30A(5):716–717.
29.
ElitLBockingAKenyonCNataleR. An endodermal sinus tumor diagnosed in pregnancy: case report and review of the literature. Gynecol Oncol. 1999;72(1):123–127.
30.
ArangoHAKalterCSDecesareSLFioricaJVLymanGHSpellacyWN. Management of chemotherapy in a pregnancy complicated by a large neuroblastoma. Obstet Gynecol. 1994;84(4 pt 2):665–668.
31.
GermannNGoffinetFGoldwasserF. Anthracyclines during pregnancy: embryo-fetal outcome in 160 patients. Ann Oncol. 2004;15(1):146–150.
32.
SymeMRPaxtonJWKeelanJA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet. 2004;43(8):487–514.
33.
GligorovJLotzJP. Preclinical pharmacology of the taxanes: implications of the differences. Oncologist. 2004;9(suppl 2):3–8.
34.
GianniLViganoLLocatelliA. Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol. 1997;15(5):1906–1915.
35.
SmitJWHuismanMTvan TellingenOWiltshireHRSchinkelAH. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest. 1999;104(10):1441–1447.
36.
MirOBerveillerPGoffinetF. Taxanes for breast cancer during pregnancy: a systematic review. Ann Oncol. 2010;21(2):425–426.
37.
ChunKCKimDYKimJHKimYMKimYTNamJH. Neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical surgery in early cervical cancer during pregnancy: three case reports. Jpn J Clin Oncol. 2010;40(7):694–698.
38.
PeregDKorenGLishnerM. Cancer in pregnancy: gaps, challenges and solutions. Cancer Treat Rev. 2008;34(4):302–312.
39.
PeccatoriFAAzimHAJrScarfoneG. Weekly epirubicin in the treatment of gestational breast cancer (GBC). Breast Cancer Res Treat. 2009;115(3):591–594.
40.
Kopf-MaierP. Stage of pregnancy-dependent transplacental passage of 195mPt after cis-platinum treatment. Eur J Cancer Clin Oncol. 1983;19(4):533–536.
41.
MirOBerveillerPRopertSGoffinetFGoldwasserF. Use of platinum derivatives during pregnancy. Cancer. 2008;113(11):3069–3074.
42.
MihalyGWMorganDJ. Placental drug transfer: effects of gestational age and species. Pharmacol Ther. 1983;23(2):253–266.
43.
SastryBV. Techniques to study human placental transport. Adv Drug Deliv Rev. 1999;38(1):17–39.
44.
Ala-KokkoTIMyllynenPVähäkangasK. Ex vivo perfusion of the human placental cotyledon: implications for anesthetic pharmacology. Int J Obstet Anesth. 2000;9:26–38.
45.
MyllynenPVahakangasK. An examination of whether human placental perfusion allows accurate prediction of placental drug transport: studies with diazepam. J Pharmacol Toxicol Methods. 2002;48(3):131–138.
46.
Van CalsterenKDevliegerRDe CatteL. Feasibility of ultrasound-guided percutaneous samplings in the pregnant baboon: a model for studies on transplacental transport. Reprod Sci. 2009;16(3):280–285.
