Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier.
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Sugiyama D, Kusuhara H, Shitara Y, Abe T, Meier PJ, Sekine T, Endou H, Suzuki H, Sugiyama Y
Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier.
J Pharmacol Exp Ther. 2001 Jul;298(1):316-22.
- PubMed ID
- 11408557 [ View in PubMed]
- Abstract
The contribution of organic anion transporters to the total efflux of 17beta-estradiol-D-17beta-glucuronide (E(2)17betaG) 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. E(2)17betaG 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 microl 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 (K(i) = 0.037 microM). The K(i) values of TCA for Oatp1 and Oatp2 (11 and 39 microM, 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 microM, 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 E(2)17betaG from the brain appears to be about 40 and 20%, respectively.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Aminohippuric acid Solute carrier family 22 member 6 Protein Humans UnknownSubstrateInhibitorDetails Aminohippuric acid Solute carrier family 22 member 8 Protein Humans UnknownSubstrateInhibitorDetails Digoxin Solute carrier organic anion transporter family member 1B1 Protein Humans UnknownSubstrateInhibitorDetails Probenecid Solute carrier family 22 member 6 Protein Humans UnknownSubstrateInhibitorDetails Probenecid Solute carrier family 22 member 8 Protein Humans UnknownInhibitorDetails Probenecid Solute carrier organic anion transporter family member 1A2 Protein Humans UnknownInhibitorDetails Taurocholic acid Solute carrier family 22 member 6 Protein Humans UnknownSubstrateInhibitorDetails Taurocholic acid Solute carrier family 22 member 8 Protein Humans UnknownSubstrateInhibitorDetails Taurocholic acid Solute carrier organic anion transporter family member 1A2 Protein Humans UnknownSubstrateInhibitorInducerDetails