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Vol. 298, Issue 1, 316-322, July 2001
-Estradiol-D-17-glucuronide from the Brain across
the Blood-Brain Barrier
Department of Biopharmaceutics, Graduate School of Pharmaceutical
Sciences, The University of Tokyo, Tokyo, Japan (D.S., H.K., H.S.,
Y.Su.); Department of Pharmaceutics, School of Pharmaceutical Sciences,
Kitasato University, Kitasato, Japan (Y.Sh.); Department of
Neurophysiology, First Department of Surgery, Tohoku University School
of Medicine, Sendai, Japan (T.A.); Division of Clinical Pharmacology
and Toxicology, Department of Medicine, University Hospital Zurich,
Zurich, Switzerland (P.J.M); Department of Pediatrics, Mejirodai
Campus, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
(T.S.); and Department of Pharmacology and Toxicology, Kyorin
University School of Medicine, Tokyo, Japan (H.E.)
The contribution of organic anion transporters to the total efflux of
17
-estradiol-D-17-glucuronide (E217G)
through the blood-brain barrier (BBB) was investigated using the Brain
Efflux Index method by examining the inhibitory effects of probenecid, taurocholate (TCA), p-aminohippurate (PAH), and digoxin.
E217G was eliminated through the BBB with a rate
constant of 0.037 min
1 after the microinjection into the
brain. Probenecid and TCA inhibited this elimination with an
IC50 value of 34 and 1.8 nmol/0.5 µl of injectate,
respectively, whereas PAH and digoxin reduced the total efflux to about
80 and 60% of the control value, respectively. The selectivity of
these inhibitors was confirmed by examining their inhibitory effects on
the transport via organic anion transporting polypeptide 1 (Oatp1),
Oatp2, organic anion transporter 1 (Oat1), and Oat3 transfectants using
LLC-PK1 cells as hosts. Digoxin specifically inhibited the transport
via Oatp2 (Ki = 0.037 µM). The
Ki values of TCA for Oatp1 and Oatp2 (11 and
39 µM, respectively) were about 20 times lower than those for Oat1
and Oat3 (2.8 and 0.8 mM, respectively). PAH did not affect the
transport via the Oatp family, but had a similar affinity for Oat1 and
Oat3 (85 and 300 µM, respectively). Probenecid had a similar affinity
for these transporters (Oatp1, Oatp2, Oat1, and Oat3) examined in this
study. Taking the selectivity of these inhibitors into consideration,
the maximum contribution made by the Oatp2 and Oat family to the total
efflux of E217G from the brain appears to be about 40 and 20%, respectively.
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