Drug Metabolism and Disposition

Transcription

1 Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-drug Interactions Saki Izumi, Yoshitane Nozaki, Kazuya Maeda, Takafumi Komori, Osamu Takenaka, Hiroyuki Kusuhara, and Yuichi Sugiyama Supplemental Table 1 Kinetic parameters of inhibitors used for the calculation of R-values [I] u,inlet,max (estimated maximum unbound inhibitor concentrations at the inlet to the liver) of CsA, rifampin, and gemfibrozil were calculated by Eq. 7 as described under Materials and Methods, in which k a of 0.1 min -1, F a F g of 1, and Q h of 97 L/h were used. The blood to plasma concentration ratios of the inhibitors were assumed to be unity in the [I] u,inlet,max calculations. Inhibitors Dose f u C max [I] u,inlet,max (mg) (%) (µm) (µm) CsA 200 a 11 b 0.95 a 1.2 Rifampin 600 c 15 d 23 e 10 Gemfibrozil 600 c 0.65 f,h 100 g 1.6 a Mück et al., 1999 b Lemaire and Tillement, 1982 c Yoshida et al., 2012 d Burman et al., 2001 e Maeda et al., 2011 f Shitara et al., 2004 g Okerholm et al., 1976 h As the f u was less than 1%, the [I] u,inlet,max was calculated assuming f u of 1% based on the regulatory DDI guidelines or draft guidance materials in U.S., EU, and Japan.

2 [Title] Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-drug Interactions [Authors] Saki Izumi, Yoshitane Nozaki, Kazuya Maeda, Takafumi Komori, Osamu Takenaka, Hiroyuki Kusuhara, and Yuichi Sugiyama [Journal] Drug Metabolism and Disposition Supplemental Table 2 IC 50 values of CsA, rifampin, and gemfibrozil for OATP1B1-mediated uptake of clinically-used OATP1B1 substrate drugs OATP1B1-mediated uptake of 12 clinically-used OATP1B1 substrate drugs was examined in the presence and absence of CsA, rifampin, or gemfibrozil as shown in Fig. 3. IC 50 values (parameter estimate ± parameter S.D.) were estimated by a nonlinear least-squares regression analysis based on Eq. 3 as described under Materials and Methods (n = 6-9). Substrates Inhibitors CsA a Rifampin Gemfibrozil IC 50, µm Pitavastatin ± ± ± 11.1 Atorvastatin ± ± ± 10.1 Fluvastatin ± ± ± 10.5 Rosuvastatin ± ± ± 9.4 Pravastatin ± ± ± 3.8 Repaglinide ± ± ± 20.0 Nateglinide ± ± ± 103 Glibenclamide ± ± ± 5.7 Bosentan ± ± ± 6.0 Valsartan ± ± ± 0.4 Torasemide ± ± ± 11.3 Fexofenadine ± ± ± 4.4 a IC 50 values of CsA listed in the table were obtained by co-incubation of a substrate and CsA without CsA pre-incubation.

3 [Title] Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-drug Interactions [Authors] Saki Izumi, Yoshitane Nozaki, Kazuya Maeda, Takafumi Komori, Osamu Takenaka, Hiroyuki Kusuhara, and Yuichi Sugiyama [Journal] Drug Metabolism and Disposition Supplemental Table 3 Reported IC 50 or K i values of CsA, rifampin, and gemfibrozil for OATP1B1-mediated uptake of prototypical substrates or clinically-used OATP1B1 substrate drugs These data were retrieved from the University of Washington Metabolism and Transport Drug Interaction Database (DIDB), the University of Tokyo TP-search, and searches in PubMed. Substrates Inhibitors CsA Rifampin Gemfibrozil References Reported IC 50 or K i values, µm E 2 G 0.05, 0.13, 0.198, 0.2, 0.37, 0.87, 0.9, 1.4, 2, 5-7, 11, 18-20, 22, 0.55, 0.59, 0.6, 0.94, 1.2, 1.5, , 12.5, 27, 27.5, 41.4, , 26, 28 E 1 S , 2.65, 5.16 a 200 3, 22, 23 BSP , 17, , 14, 27 Pitavastatin 0.242, 0.7, 2.91 a 0.477, 1.6, , 38, 100 4, 8, 16, 19, 22 Atorvastatin 0.31, , 68 1, 10, 12, 19 Fluvastatin Rosuvastatin 0.31, 0.89, 2.2 a 1.1 4, 19, 25 9, 16, 17, 19-21, 26 Pravastatin a, 18, , 19 Repaglinide Nateglinide Glibenclamide Bosentan Valsartan Torasemide Fexofenadine : Not reported. a X. laevis oocyte systems. Other IC 50 or K i values were determined in OATP1B1-expressing mammalian cells.

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