Tissue distribution of YM758, a novel If channel inhibitor, in pregnant and lactating rats.
In this study the tissue distribution of radioactivity in pregnant and lactating rats was investigated by quantitatively determining radioactivity concentrations and by whole-body autoradioluminograms after a single oral administration of 14C-YM758. In addition, the transfer of radioactivity into the reproductive tissues, foetus, and milk is discussed in terms of the localization of transporters in syncytiotrophoblast and mammary gland. The radioactivity concentrations in the liver were the highest of all the tissues and organs tested at all the sampling times. The radioactivity in main tissues (liver and kidney), including reproductive tissues (amniotic fluid, placenta, ovary, and uterus), was not retained for a long time, as in the plasma. The tissue/plasma (T/P) ratio of radioactivity in the foetus was below 1.0, which might be due to Mdr1-mediated export of YM758 into blood via the blood-placenta barrier since YM758 is a substrate for hMDR1, not for hBCRP/rBcrp. The T/P ratio of radioactivity in the maternal milk 1 and 4 h after oral administration of 14C-YM758 was 7.2 and 11.0, respectively. To understand better the distribution of new drugs into the reproductive tissues/milk, and to interpret further the results of reproductive safety studies for drug development, the contribution of transporters expressed in the blood-placenta barrier and mammary gland to the drug-transfer into placenta and milk should be considered.
Umehara
K-I
KI
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan. kenichi.umehara@jp.astellas.com
Seya
K
K
Iwatsubo
T
T
Noguchi
K
K
Usui
T
T
Kamimura
H
H
D000284:Administration, Oral; D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005836:Genitalia, Female / Q000378:metabolism*; D007546:Isoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D007774:Lactation / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000737:chemistry*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D001549:Benzamides; D007546:Isoquinolines; C530155:YM 758