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Tricyclic compounds inhibit the OATP1A2 transporter
Author(s) -
Lu Jennifer,
Moya Liliam Gabriela Guilarte,
Leung Yat Hei,
Gaudette Fleur,
Turgeon Jacques
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.674.2
Subject(s) - tricyclic , chemistry , pharmacology , nortriptyline , rosuvastatin , doxepin , stereochemistry , amitriptyline , medicine
Background OATP1A2 is a membrane transporter potentially involved in the absorption of various drugs. Previous data demonstrated that the uptake of rosuvastatin through OATP1A2 can be inhibited by several β‐blockers, where carvedilol is the most potent inhibitor. Carvedilol structurally differs from the other β‐blockers tested by its tricyclic moiety. The goal of this study was to determine whether the tricyclic structure of carvedilol is responsible for its strong inhibitory effect on OATP1A2. Methods A HEK293 cell line overexpressing OATP1A2 was used as model. They were co‐incubated in the presence of rosuvastatin and increasing concentrations of different tricyclic compounds. The amount of rosuvastatin transported in the cells was measured by HPLC. Results Most tricyclic compounds evaluated inhibited rosuvastatin uptake through OATP1A2 with different IC 50 . Our data show that the inhibition is competitive.Compound IC 50 (μM) Compound IC 50 (μM)carazolol 4.0 nortriptyline 14.8 amitriptyline 5.0 chlorpromazine 29.6 imipramine 12.6 desipramine 77.9 trimipramine 13.6 carbamazepine >;100 doxepin 14.0 carbazole No effect clomipramine 14.7 phenothiazine No effectConclusions The inhibitory component is made up of the tricyclic ring with a short aliphatic chain. Consequently, drugs with a similar structure may strongly modulate the transport of OATP1A2 substrates. Funding: CIHR, FRSQ, Foundation CHUM