Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport

Abstract

The effects of different fibric acid derivatives (bezafibrate, clofibrate, clofibric acid, fenofibrate, fenofibric acid and gemfibrozil) on human organic anion transporting-polypeptide 1B1 (OATP2, OATP-C, SLC21A6), multidrug resistance protein 2 (MRP2/ABCC2) and MDR1-type P-glycoprotein (P-gp/ABCB1) were examined in vitro. Cyclosporin A (a known inhibitor of OATP1B1 and P-gp), MK-571 (a known inhibitor of MRP2) and cimetidine (an organic cation) were also tested. Bezafibrate, fenofibrate, fenofibric acid and gemfibrozil showed concentration-dependent inhibition of estradiol 17-beta-D-glucuronide uptake by OATP1B1-stably transfected HEK cells, whereas clofibrate and clofibric acid did not show any significant effects up to 100 microM. Inhibition kinetics of gemfibrozil, which exhibited the most significant inhibition on OATP1B1, was shown to be competitive with a Ki = 12.5 microM. None of the fibrates showed any significant inhibition of MRP2-mediated transport, which was evaluated by measuring the uptake of ethacrynic acid glutathione into MRP2-expressing Sf9 membrane vesicles. Only fenofibrate showed moderate P-gp inhibition as assessed by measuring cellular accumulation of vinblastine in a P-gp overexpressing cell-line. Cyclosporin A significantly inhibited OATP1B1 and P-gp, whereas only moderate inhibition was observed on MRP2. The rank order of inhibitory potency of MK-571 was determined as OATP1B1 (IC50: 0.3 microM) > MRP2 (4 microM) > P-gp (25 microM). Cimetidine did not show any effects on these transporters. In conclusion, neither MRP2- nor P-gp-mediated transport is inhibited significantly by the fibrates tested. Considering the plasma protein binding and IC50 values for OATP1B1, only gemfibrozil appeared to have a potential to cause drug-drug interactions by inhibiting OATP1B1 at clinically relevant concentrations.

In Vitro Evaluation of Hepatic Transporter-Mediated Clinical Drug-Drug Interactions: Hepatocyte Model Optimization and Retrospective Investigation

“…To meet these criteria, we measured rosuvastatin uptake in SCHHs coincubated with several known OATP transporter inhibitors. Under the concentrations applied, these inhibitors can completely block OATP1B1 or OATP1B3 activity in OATP gene overexpression systems (Vavricka et al, 2002;Yamazaki et al, 2005;Letschert et al, 2006). As a result, Rif SV (100 ⌴) was shown to completely knock down rosuvastatin uptake in SCHHs.…”

The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism

“…Figure 6 shows that after a 15-minute incubation in SCRHs, the BEI of TB-2 ranged from 43.1 to 44.9%, indicating that biliary excretion plays an important role in TB-2 hepatobiliary disposition. The Bcrp inhibitor Ko143 and Mrp2 inhibitor MK-571 (Yamazaki et al, 2005;Weiss et al, 2007) significantly decreased the TB-2 BEI values from 44.9 to 12.7% (Fig. 6A) and 43.1 to 15.2% (Fig.…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…OATP1B1 transports pravastatin (Nakai et al, 2001). OATP1B1 transport is inhibited by fibric acid derivatives and may contribute to known drug-drug interactions, such as gemfibrozil-cerivastatin (Shitara et al, 2004;Yamazaki et al, 2005) and rifampin-atorvastatin (Lau et al, 2007). In contrast, rosuvastatin can be transported by a number of OATP isoforms, including OATP1B1, -1B3, -2B1, and -1A2 as well as rat Oatp1a1, -1a4, -1a5, and -1b2, probably reducing the chance of drug-drug interactions (Ho et al, 2006b).…”