PMID- 37981232
OWN - NLM
STAT- MEDLINE
DCOM- 20240202
LR  - 20240305
IS  - 1520-6017 (Electronic)
IS  - 0022-3549 (Linking)
VI  - 113
IP  - 2
DP  - 2024 Feb
TI  - Breast Cancer Resistance Protein Limits Fetal Transfer of Tadalafil in Mice.
PG  - 486-492
LID - S0022-3549(23)00480-X [pii]
LID - 10.1016/j.xphs.2023.11.006 [doi]
AB  - Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, is a candidate therapeutic 
      agent for fetal growth restriction and hypertensive disorders of pregnancy. In 
      this study, we elucidated the fetal transfer of tadalafil in comparison with that 
      of sildenafil, the first PDE5 inhibitor to be approved. We also examined the 
      contributions of multidrug resistance protein 1 (MDR1) and breast cancer 
      resistance protein (BCRP) to fetal transfer. Tadalafil or sildenafil was 
      administered to wild-type, Mdr1a/b-double-knockout or Bcrp-knockout pregnant mice 
      by continuous infusion from gestational day (GD) 14.5 to 17.5, and the 
      fetal-to-maternal plasma concentration ratio of unbound drug (unbound F/M ratio) 
      was evaluated at GD 17.5. The values of unbound F/M ratio of tadalafil and 
      sildenafil in wild-type mice were 0.80 and 1.6, respectively. The unbound F/M 
      ratio of tadalafil was increased to 1.1 and 1.7 in Mdr1a/b-knockout and 
      Bcrp-knockout mice, respectively, while the corresponding values for sildenafil 
      were equal to or less than that in wild-type mice, respectively. A transcellular 
      transport study revealed that basal-to-apical transport of both tadalafil and 
      sildenafil was significantly higher than transport in the opposite direction in 
      MDCKII-BCRP cells. Our research reveals that tadalafil is a newly identified 
      substrate of human and mouse BCRP, and it appears that the fetal transfer of 
      tadalafil is, at least in part, attributed to the involvement of BCRP within the 
      placental processes in mice. The transfer of sildenafil to the fetus was not 
      significantly constrained by BCRP, even though sildenafil was indeed a 
      substantial substrate for BCRP.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Nishimura, Tomohiro
AU  - Nishimura T
AD  - Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 
      105-8512, Japan. Electronic address: nishimura-tm@pha.keio.ac.jp.
FAU - Ishii, Mari
AU  - Ishii M
AD  - Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 
      105-8512, Japan; PV Operations Management Department, Clinical Safety & 
      Pharmacovigilance Division, Daiichi Sankyo Co., Ltd., Japan.
FAU - Tanaka, Hiroaki
AU  - Tanaka H
AD  - Department of Obstetrics and Gynecology, Mie University Graduate School of 
      Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
FAU - Noguchi, Saki
AU  - Noguchi S
AD  - Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 
      105-8512, Japan.
FAU - Ikeda, Tomoaki
AU  - Ikeda T
AD  - Department of Obstetrics and Gynecology, Mie University Graduate School of 
      Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
FAU - Tomi, Masatoshi
AU  - Tomi M
AD  - Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 
      105-8512, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231121
PL  - United States
TA  - J Pharm Sci
JT  - Journal of pharmaceutical sciences
JID - 2985195R
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (Phosphodiesterase 5 Inhibitors)
RN  - BW9B0ZE037 (Sildenafil Citrate)
RN  - 742SXX0ICT (Tadalafil)
RN  - 0 (Abcg2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Female
MH  - Humans
MH  - Mice
MH  - Pregnancy
MH  - *ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/metabolism
MH  - Mice, Knockout
MH  - *Phosphodiesterase 5 Inhibitors/pharmacokinetics
MH  - *Placenta/metabolism
MH  - *Sildenafil Citrate/pharmacokinetics
MH  - *Tadalafil/pharmacokinetics
MH  - *Maternal-Fetal Exchange
OTO - NOTNLM
OT  - BCRP
OT  - Fetal transfer
OT  - MDR1
OT  - Placental barrier
OT  - Sildenafil
OT  - Tadalafil
COIS- Declaration of Competing Interest M. Ishii, the second author, was hired by 
      Daiichi Sankyo Co., Ltd. after this study was completed. No authors received 
      financial or any other support, including materials, from Daiichi Sankyo Co., 
      Ltd. for this study.
EDAT- 2023/11/20 00:43
MHDA- 2024/01/22 06:42
CRDT- 2023/11/19 19:32
PHST- 2023/10/05 00:00 [received]
PHST- 2023/10/25 00:00 [revised]
PHST- 2023/11/08 00:00 [accepted]
PHST- 2024/01/22 06:42 [medline]
PHST- 2023/11/20 00:43 [pubmed]
PHST- 2023/11/19 19:32 [entrez]
AID - S0022-3549(23)00480-X [pii]
AID - 10.1016/j.xphs.2023.11.006 [doi]
PST - ppublish
SO  - J Pharm Sci. 2024 Feb;113(2):486-492. doi: 10.1016/j.xphs.2023.11.006. Epub 2023 
      Nov 21.