Functional Identification of Plasma Membrane Monoamine Transporter (PMAT/SLC29A4) as an Atenolol Transporter Sensitive to Flavonoids Contained in Apple Juice

Abstract

The intestinal absorption of atenolol has recently been reported to be reduced by simultaneous ingestion of fruit juices, such as apple juice. This finding implies a possibility that an unidentified carrier-mediated transport system, which could be interfered by some components of those juices, might be involved in atenolol absorption. In an attempt to explore that possibility, we successfully identified plasma membrane monoamine transporter (PMAT/SLC29A4) as a transporter that can operate for cellular atenolol uptake in the intestine, using Madin-Darby canine kidney II cells stably expressing PMAT. The specific uptake of atenolol by PMAT was greatest at around pH 6.0 and decreased with an increase in pH. At pH 6.0, the PMAT-specific uptake of atenolol was saturable with a Michaelis constant of 0.907 mM. Moreover, PMAT-specific atenolol uptake was extensively inhibited by phloretin and quercetin, which are the major flavonoids contained in apple juice, with the half maximal inhibitory concentrations of 33.3 and 116.3 μM, respectively. PMAT-specific atenolol uptake was also inhibited by several ß-blockers, suggesting that they may also be recognized and transported by PMAT. These results suggest that PMAT is an atenolol transporter that may be involved in intestinal atenolol absorption and sensitive to flavonoids contained in apple juice.

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.…”

Constitutive plasma membrane monoamine transporter (PMAT, Slc29a4) deficiency subtly affects anxiety‐like and coping behaviours

“…Multiple research groups have continued to explore cation transport by PMAT at the blood-brain barrier, particularly at the choroid plexus (Duan & Wang, 2013;Hu, Zha, Duan, & Wang, 2017;Okura et al, 2011;Usui et al, 2016;Wu, Lu, Peng, Hsu, & Lin, 2015). PMAT is also suspected to contribute to intestinal transport and accumulation of cationic drugs, such as metformin and atenolol, and this is supported by in vitro evidence (Han et al, 2015;Mimura et al, 2017;Wagner et al, 2016;. Continued study of PMAT's gastrointestinal contributions, particularly given the reduced defecation that we observed as a function of PMAT deficiency, could expand investigative avenues for this protein beyond drug absorption into the realm of gastrointestinal disorders.…”

“…Black squares, grey diamonds and white circles indicate individual data points for wild-type, heterozygous and knockout animals, respectively genotype on faecal boli after 4-hr in the locomotor assay, with PMAT deficiency appearing to reduce faecal boli in a lowstress condition. Given the evidence of PMAT expression in the intestines (Han et al, 2015;Mimura, Yasujima, Ohta, Inoue, & Yuasa, 2017;Wagner, Hu, & Wang, 2016;, this reduced faecal output may be an indicator of altered digestive functionality rather than an indicator of stress response. In sum, constitutive deficiency of PMAT in mice produces remarkably mild effects on anxietyrelated behaviours and enhances active-coping behaviours specifically in female knockouts.…”

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.…”