Evaluation of rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion

Tomohiro Nishimura, Tatsuya Takanohashi, Masatoshi Tomi, Miho Horikoshi, Kei Higuchi, Yoshimichi Sai, Emi Nakashima

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

It is important to address the tissue permeability of drugs, particularly in tissues that have a blood-tissue barrier, in terms of both lipophilicity and the contribution of transporters. Here, we employed umbilical perfusion in rats to evaluate in vivo fetal-to-maternal transfer clearances of various xenobiotics. We measured fetal-to-maternal clearance (CLfm) of 23 compounds, which have a broad range of lipophilicity. Drugs for which CLfm was more than 300 μL/(mL min) belonged exclusively to Biopharmaceutical Drug Disposition Classification System (BDDCS) class 1 (highly permeable) and those for which CLfm was less than 50 μL/(mL min) belonged exclusively to BDDCS class 3 (poorly permeable). For most drugs, CLfm values were broadly consistent with lipophilicity. However, CLfm of digoxin was saturable and was inhibited by verapamil, suggesting that P-glycoprotein (P-gp)-mediated efflux has a substantially effect on measured clearance. CLfm of mitoxantrone continued to increase slightly at high concentrations of mitoxantrone, but placental-to-maternal clearance of mitoxantrone was saturable, implying that Bcrp1 contributes to mitoxantrone efflux across the placenta. Thus, we measured CLfm by umbilical perfusion and examined the relationship between CLfm and lipophilicity of xenobiotics. Fetal-to-maternal transport clearances measured in this study will be helpful to understand the characteristics of the blood-placental barrier.

Original languageEnglish
Pages (from-to)3356-3363
Number of pages8
JournalJournal of Pharmaceutical Sciences
Volume102
Issue number9
DOIs
Publication statusPublished - 2013 Sep

Fingerprint

Umbilicus
Xenobiotics
Mitoxantrone
Perfusion
Mothers
Pharmaceutical Preparations
Digoxin
P-Glycoprotein
Verapamil
Placenta
Permeability

Keywords

  • Active transport
  • Biopharmaceutics classification system (BCS)
  • Clearance
  • Drug transport
  • Efflux pumps
  • Kinetics
  • Log P
  • Placenta
  • Pregnancy

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Evaluation of rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion. / Nishimura, Tomohiro; Takanohashi, Tatsuya; Tomi, Masatoshi; Horikoshi, Miho; Higuchi, Kei; Sai, Yoshimichi; Nakashima, Emi.

In: Journal of Pharmaceutical Sciences, Vol. 102, No. 9, 09.2013, p. 3356-3363.

Research output: Contribution to journalArticle

Nishimura, Tomohiro ; Takanohashi, Tatsuya ; Tomi, Masatoshi ; Horikoshi, Miho ; Higuchi, Kei ; Sai, Yoshimichi ; Nakashima, Emi. / Evaluation of rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion. In: Journal of Pharmaceutical Sciences. 2013 ; Vol. 102, No. 9. pp. 3356-3363.
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