Effects of β-Blockers and Tricyclic Antidepressants on the Activity of Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2)

Abstract

The organic anion transporting polypeptide 1A2 (OATP1A2), a membrane drug transporter expressed on important organs (such as the brain, kidney, and intestine) may be a key element in the disposition of drugs. Previous studies demonstrated that it could transport a broad spectrum of substrates, including endogenous molecules and clinically relevant drugs, such as several b-blockers and 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. The primary objective of this study was to investigate OATP1A2 transport activity using rosuvastatin as a probe substrate and evaluate competitive inhibition of its transport by b-blockers. Rosuvastatin transport was saturable, with a K m of 60.2 mM. With the exception of carvedilol (IC 50 of 3.2 mM), all of the other b-blockers that were evaluated had a small or insignificant effect on OATP1A2-mediated uptake of rosuvastatin. Carvedilol differs from the other b-blockers by the tricyclic moiety in its chemical structure. As a secondary objective, the transport of a series of tricyclic compounds by OATP1A2 and their potential for rosuvastatin transport inhibition were evaluated. Tricyclic compounds were not OATP1A2 substrates. On the other hand, tricyclic compounds with a short aliphatic amine chain inhibited OATP1A2-mediated rosuvastatin transport. Our data suggest that these drugs may modulate the transport of OATP1A2 substrates and may affect drug actions.

Inhibition of Intestinal OATP2B1 by the Calcium Receptor Antagonist Ronacaleret Results in a Significant Drug-Drug Interaction by Causing a 2-Fold Decrease in Exposure of Rosuvastatin

“…Following removal of preincubation solution, 400 ml of HBSS supplemented with 10 mM HEPES (OATP1B1 only) or DPBS containing ronacaleret at the previously listed target concentrations and 1 mM (OATP1B1, OATP1B3, and OATP2B1) or 5 mM (OATP1A2) rosuvastatin was added to the wells in triplicate. Rosuvastatin substrate concentrations for these transporters in the present study were lower than the published K m values (van de Steeg et al, 2013;Bosgra et al, 2014;Lu et al, 2015). Cells were incubated at 37°C for 3 minutes for OATP1B1, OATP1B3, and OATP1A2 and for 10 minutes for OATP2B1.…”

Gastrointestinal Malabsorption of Thyroxine

“…The authors postulated an effect on T4 elimination from enterocytes, and not on T4 absorption, that may impair the hormonal enterohepatic recycling and thus bioavailability (35). The evidence that β-blockers and tricyclic antidepressants may use this same transporter shed light on a novel site of interaction with thyroxine (76). A similar involvement in the process of recycling of thyroid hormones from ileum to the liver has been proposed also for OATP4A1, through the portal vein (77).…”

Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice

“…For example, orange juice and apple juice have been shown to reduce significantly the systemic exposure to fexofenadine, some beta‐blockers, and aliskiren by at least 50% . More recently, constituents in a green tea beverage were reported to decrease systemic exposure to the beta‐blocker, nadolol, by 85% in healthy volunteers by inhibiting intestinal OATP1A2, albeit the existence of this transporter is controversial ; this reduction in systemic exposure was accompanied by an attenuated reduction in systolic blood pressure . These observations prompted evaluation of a streamlined approach for pre‐clinical testing of candidate intestinal OATP inhibitors using grapefruit juice as an archetypal, well‐characterized natural product with successful in vitro – in vivo extrapolated drug interaction liability.…”