TABLE 1

Comparison of Ki values of inhibitors for OATP1B1-mediated uptake of pitavastatin and OATP1B3-mediated uptake of FEX

Ki values are expressed as the mean ± computer-calculated S.D. The inhibitors, which are shown in boldface, increased the plasma AUC in the previous clinical studies. Data for dosages, Imax, and fu are from product information of each drug except for the data with footnotes. R and Iin, max values are calculated according to eq. 2 and eq. 3, respectively (see Materials and Methods).

Inhibitor Dosage ImaxIin, maxfu OATP1B3 OATP1B1
KiRKi a R
mg μM μM μM μM
Cyclosporin A 100 0.596 5.76 0.10b 0.573 ± 0.172 2.01 0.242 ± 0.029 3.55
Rifampicin 600c 7.90c 53.2 0.11c 1.45 ± 0.28 5.03 0.477 ± 0.030 13.3
Fluconazole 100 8.62 28.9 0.89c >100 <1.26 >100 <1.26
Itraconazole 100 0.0792 8.88 0.002c >30 1.00 >100 1.00
Ketoconazole 200c 3.20c 26.6 0.01c 18.5 ± 3.0 1.01 19.2 ± 3.9 1.01
Clarithromycin 400 1.86 35.1 0.54c 53.6 ± 15.9 1.42 8.26 ± 0.54 3.29
Erythromycin 200 1.12 18.0 0.16c 38.3 ± 7.7 1.08 11.4 ± 2.1 1.25
Azithromycin 1200 0.881 100 0.84 161 ± 7.7 1.52 N.D.
Ritonavir 800 28.5 97.4 0.02c 5.64 ± 1.39 1.35 0.781 ± 0.048 3.49
Lopinavir 400 15.2 54.8 0.015 18.4 ± 7.2 1.04 N.D.
Probenecid 2000d 52.0d 487 0.10c 130 ± 40e 1.37 76.2 ± 7.1 1.64
Diltiazem 100 0.0536 15.0 0.22c 193 ± 112 1.03 >100 <1.03
Verapamil 80 0.190 11.1 0.10c 89.5 ± 52.9 1.01 51.6 ± 15.9 1.02
Omeprazole 20 1.18 4.77 0.03 53.9 ± 14.3 1.00 N.D.
Cimetidine 200 2.75 52.0 0.81c >100 <1.42 >300 <1.14
  • N.D., not determined.

  • a Ki values of inhibitors for the OATP1B1-mediated uptake of pitavastatin were determined previously (Hirano et al., 2006).

  • b Data for protein unbound fraction of cyclosporin A are from a previous report (Lemaire and Tillement, 1982).

  • c These data are from Hardman and Limbard (2001).

  • d Data for dosages and Imax of probenecid are from a previous report (Selen et al., 1982).

  • e Ki values of probenecid were determined previously (Tahara et al., 2006).