Involvement of Renal Efflux Transporter MATE1 in Renal Excretion of Flecainide

Abstract

Flecainide, an anti-arrhythmic drug, undergoes renal excretion through active renal tubular secretion in addition to passive glomerular filtration. The contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide remains unclear except that flecainide is a substrate of human multidrug resistance protein 1 (MDR1). To elucidate renal efflux and uptake transporters involved with active renal tubular secretion of flecainide, we conducted in vitro interaction studies of flecainide using organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, and MATE2-K. Uptake transporter inhibition assays using hOCT2-Chinese hamster ovary (CHO), hMATE1-CHO, and hMATE2-K-Madin Darby canine kidney strain II (MDCKII) cells revealed that flecainide (2.5 µM) inhibited hMATE1-mediated transport by 40% with an IC 50 value of 6.7 µM; however, it showed no or weak inhibitory effects on hOCT2-and hMATE2-K-mediated transport. For investigating flecainide as a substrate of hMATE1, the accumulation of flecainide in hMATE1-CHO was compared with that in control cells. Uptake transporter substrate assay revealed that flecainide (1 µM) showed 1.11-fold accumulation though the hMATE1-related active transport was significantly decreased in the presence of quinidine (42.0 23.9 vs. 11.8 4.1 pmol/mg in transfected cells; p < 0.05). These results suggest that flecainide is a weak substrate of hMATE1, which is involved in the renal tubular secretion of cationic drugs, and hMATE1 may be less important in the pharmacokinetic drug-drug interaction for renal excretion of flecainide. However, in vivo drug-drug interaction studies of flecainide with substrates of hMATE1 may be needed because flecainide has the potential to inhibit hMATE1.

Assessing Transporter‐Mediated Natural Product‐Drug Interactions Via In vitro‐In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail

“…Test articles as inhibitors of transporters. Inside-out membrane vesicles prepared from HEK293 cells overexpressing a single transporter (vesicular transport inhibition assay) or cell lines (HEK293 and MDCKII) stably expressing a single transporter (uptake transporter inhibition) were used to determine the inhibitory effects of each test article on the designated transporter as described [21][22][23] using established probe substrates and inhibitors (Table S4). Each alkaloid was tested at 10 and 100 µM, whereas the goldenseal extract, standardized to berberine concentrations (detailed above), was tested at 1.75 µM and 17.5 µM (based on solubility limits).…”

“…Participants who completed the study self-identified as white (7 men and 6 women) or Asian (1 man and 2 women). The median (range) age was 27 (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) and 26 (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) for men and women, respectively. None of the participants reported taking concomitant medications or NPs known to modulate the metabolism of midazolam and disposition of the remaining probe drugs.…”

Farmácia: fronteiras na pesquisa e desenvolvimento 4

“…A excreção renal de medicamentos é um processo dinâmico e pode ser afetada por diversos fatores, como a função renal, o pH urinário, o fluxo sanguíneo renal, a idade e o sexo do paciente. Alterações na função renal podem ter um impacto significativo na excreção de medicamentos, podendo resultar em acúmulos tóxicos ou em níveis subterapêuticos no sangue (DOKI et al, 2019).…”