Enhanced efficiency of the placental barrier to cisplatin through binding to glycocholic acid.
OBJECTIVE
Cisplatin is a well known cytostatic drug, with high efficiency against several solid tumours, among which ovarian cancer diagnosed during pregnancy can be included. The existence of carrier proteins in the plasma membrane of the trophoblast determines vectorial bile acid transfer across the placenta. Thus, the aim of the present work was to elucidate whether the coupling of cisplatin to a bile acid moiety, such as cholylglycinate, could endow the resulting drug, Bamet-R2, with enhanced beneficial properties; namely, the ability of the placenta to prevent the passage of the drug toward the foetal compartment.


METHODS
On days 15 and 18 of gestation, pregnant rats were anaesthetised with ether and intravenous administration of 1 micromol cisplatin or Bamet-R2 was carried out. Following euthanasia on day 21 of pregnancy, samples from the placenta and maternal and foetal kidney, liver, brain, lung, heart, muscle and blood were collected and digested to measure tissue drug content by flameless atomic absorption spectroscopy of platinum.


RESULTS
In addition to the beneficial properties of Bamet-R2 as regards its much lower toxicity than cisplatin, this study revealed the markedly different abilities of cisplatin and Bamet-R2 to cross the placenta, which accounts for higher accumulation of cisplatin in foetal tissues: mainly kidney, lung and heart. Moreover, the amount of drug that was found in the placenta itself was several-folds higher in animals treated with cisplatin than in those receiving Bamet-R2.


CONCLUSIONS
The ability of the placental barrier to more efficiently protect the foetal compartment from cisplatin when the drug was coupled to cholylglycinate suggests the potential usefulness of Bamet-R2 as an alternative cytostatic drug in the treatment of certain tumours during pregnancy.
Pascual
M J
MJ
Department of Physiology and Pharmacology, Faculty of Pharmacy, University of Salamanca, Spain.
Macias
R I
RI
Garcia-Del-Pozo
J
J
Serrano
M A
MA
Marin
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000378:metabolism; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D014018:Tissue Distribution; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C408382:diamminebis(ursodeoxycholate(O,O'))platinum(II); D014580:Ursodeoxycholic Acid