Abstract
Atenolol, a β1-adrenergic receptor blocker, is administered orally and its intestinal absorption has recently been indicated to be mediated by carrier protein and reduced markedly by ingestion of some fruit juices, such as apple and orange juices. This could be postulated to be a problem arising from the interaction of some components of fruit juices with atenolol at a transporter involved in its intestinal uptake, but the responsible transporter and its interacting components have not been identified yet. In an attempt to examine that possibility, we could successfully find that human organic cation transporter 1 (OCT1/SLC22A1), which is suggested to be expressed at the brush border membrane of enterocytes, is highly capable of transporting atenolol. In this attempt, OCT1 was stably expressed in Madin-Darby canine kidney II cells and the specific uptake of atenolol by the transporter was found to be saturable, conforming to the Michaelis-Menten kinetics with the maximum transport rate (Vmax) of 4.00 nmol/min/mg protein and the Michaelis constant (Km) of 3.08mM. Furthermore, the OCT1-specific uptake was found to be inhibited by various flavonoids, including those contained in fruit juices that have been suggested to interfere with intestinal atenolol absorption. Particularly, phloretin and quercetin, which are major components of apple juice, were potent in inhibiting OCT1-mediated atenolol transport with the inhibition constants of 38.0 and 48.0µM, respectively. It is also notable that the inhibition by these flavonoids was of the noncompetitive type. These results indicate that OCT1 is an atenolol transporter that may be involved in intestinal atenolol uptake and sensitive to fruit juices, although its physiological and clinical relevance remains to be further examined.
Highlights
Atenolol, a β1-adrenergic receptor blocker, is administered orally and its intestinal absorption has recently been indicated to be mediated by carrier protein and reduced markedly by ingestion of some fruit juices, such as apple and orange juices
Madin-Darby canine kidney II (MDCKII) cells and human embryonic kidney 293 (HEK293) cells were maintained at 37 °C and 5% CO2 in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% Fetal bovine serum (FBS), 100 U/ml penicillin, and 100 mg/ml streptomycin
MDCKII cells were transfected with the plasmid carrying the cDNA of OCT1 by using Lipofectamine 2000 (Invitrogen) as a transfection reagent, according to the manufacturer’s instructions, and cultured in DMEM supplemented with 10% FBS and 400 mg/ml G418 for 2 or 3 weeks
Summary
SLCO1A2) and OATP2B1/SLCO2B1, which have recently been suggested to be involved in the intestinal uptake of various anionic drugs [9], can be inhibited by such plant components, and it could lead to decreases in the absorption of their substrate drugs [10,11]. It should be of interest to note that some β1-adrenergic receptor blockers structurally analogous to atenolol have been reported to be transported by OATP1A2 and OATP2B1 [12,13], even though this class of drugs is cationic. OATP1A2 and OATP2B1 may contribute to the absorption of atenolol, but another possibility could not be excluded that some other transporters for cationic compounds may participate in that process. Its presence and potential role in drug transport has been suggested in the intestine in the brush border and basolateral membranes
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