Functional identification of organic cation transporter 1 as an atenolol transporter sensitive to flavonoids

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 3.08 mM. 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 48.0 µM, 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.

Effect of Osmolality on the Pharmacokinetic Interaction between Apple Juice and Atenolol in Rats

“…Because OCT1 and PMAT are reportedly inhibited by phloretin and quercetin, which are major constituent flavonoids of AJ, these molecules are candidates for the key determinant of such interactions. However, the concentrations of phloretin (0.233 mM) and quercetin (0.464 mM) in AJ are below the IC 50 values for OCT1 (38.0 and 48.0 mM, respectively) and PMAT (33.3 and 116.3 mM, respectively) (Shirasaka et al, 2013;Mimura et al, 2015Mimura et al, , 2017. Therefore, it is unlikely that these flavonoids are major contributors to OCT1-and PMAT-mediated atenolol interactions involving AJ.…”

“…1). On the other hand, atenolol is reported to be a substrate of OCT1/SLC22A1 and PMAT/SLC29A4, both of which are expressed in the intestine (Mimura et al, 2015(Mimura et al, , 2017. Because OCT1 and PMAT are reportedly inhibited by phloretin and quercetin, which are major constituent flavonoids of AJ, these molecules are candidates for the key determinant of such interactions.…”

Oxidative Tea Polyphenols Greatly Inhibit the Absorption of Atenolol

“…This small size would allow for paracellular absorption and transport through membrane carriers as well ( Lennernas et al, 1994 ). The transport of atenolol across the intestinal epithelium may be mediated by the solute carrier OCT1 ( Mimura et al, 2015 ). OTP may decrease the absorption of atenolol by regulating the expression of drug receptor, but the present study could not confirm this conjecture.…”

Physicochemical QSAR Analysis of Passive Permeability Across Caco-2 Monolayers

“…Some of these compounds inhibit cellular uptake of standard substrates of several OCTs and OCTNs, 43 and atenolol itself exhibits saturable uptake by OCT1. 44,45 There is less such evidence for metoprolol, but it has comparable permeability to a similar drug propranolol despite being 1.5 units less lipophilic and having almost identical pKa and hydrogen bonding pattern. 8 Therefore, available data indicate that metoprolol is very likely to cross the cell layer by the means of facilitated diffusion, at least at conditions close to physiological.…”