TABLE 8

Example of the possible involvement of P-gp with clinical drug-drug interactions

Inhibitor or Inducer Inhibited or Induced Drug Possible Mechanisms of Drug-Drug Interactions Reference
IC50 or Ki in vitro (μM) a Dose (mg) AUC Cmax BA CL T½ Others
Mean Range b
Inhibition -fold
     Valspodar 0.182 0.022-0.41 400 Digoxin CLr −62% A Kovarik et al., 1999
Paclitaxel 2.5 Sikic et al., 2000
400 Dexamethasone 1.24 Kovarik et al., 1998
     Erythromycin 105 10-200 500 Atrovastatin 1.32 1.38 NS B Siedlik et al., 1999
1500 Digoxin 2.04 A Maxwell et al., 1989
2000 Talinolol 1.34 NS A Schwarz et al., 2000
Fexofenadine 2.09 1.82 A Davit et al., 1999
1000 Saquinavir 1.99 2.06 B Grub et al., 2001
1000 Cyclosporine 1.97 2.13 CL −38% NS Met% in plasma −49% B Freeman et al., 1987
2000 Cyclosporine 2.15 2.8 36→60% NS B Gupta et al., 1988
2000 Cyclosporine 2.15 36→60% CL −13% B Gupta et al., 1989
     Verapamil 83.1 3-236 240 Digoxin 1.44 CLbile −43%, CLr, NS A Hedman et al., 1991
160 Digoxin 1.4 A Mackstaller and Alpert, 1997
240 Digoxin 1.6-1.8 A Cobbe, 1997
     Itraconazole 200 Digoxin 1.5 CLr −20% A Jalava et al., 1997
200 Quinidine 2.4 1.6 CLr −50% ×1.6 M/P(AUC) −50% B Kaukonen et al., 1997
     Cyclosporine 7.24 3.4-17 1050 Docetaxel 11.2 8→90% B Malingre et al., 2001b
1050 Paclitaxel 8 ×8 B Meerum Terwogt et al., 1999
180-540 Paclitaxel 1 1 Britten et al., 2000
280 Sirolimus 1.45 1.71 B Kaplan et al., 1998
16 mg/kg infusion Doxorubicin 1.8 CL −37% NS M/P(AUC) −75% B Rushing et al., 1994
5-21 mg/kg Etoposide 1.59 CLtot −35% ×1.73 Lum et al., 1992
     GF120918 1000 Paclitaxel 7 ×7 B Malingre et al., 2001a
800 Doxorubicin 1 CLr NS Sparreboom et al., 1999
     Quinidine 62.8 1.5-157 Digoxin 2 CLtot −50% A Yu, 1999
800 Digoxin 1.54 CLbile −42%, CLr −29% A Hedman et al., 1990
     Quinine 280 750 Digoxin 1.1 CLbile −35% A Hedman et al., 1990
     Ketoconazole 18.8 1.5-36 Fexofenadine 2.64 2.35 A Davit et al., 1999
400 Saquinavir 2.9 2.71 B Grub et al., 2001
200 Saquinavir 1.69 1.36 B Grub et al., 2001
200 Tacrolimus 2 14→30% CL, Fh, NS B Floren et al., 1997
     Propafenone 600 Digoxin −fold CLtot −31%, CLr −32% A Calvo et al., 1989
     Clarithromycin Digoxin CLr −48% A Wakasugi et al., 1998
     Vitamin E Cyclosporine 1.61 1.37 M/P(AUC) NS C Chang et al., 1996
     Talinolol 100 Digoxin 1.23 1.45 CLr NS NS A Westphal et al., 2000a
     Ritonavir 300 Saquinavir 58 33 B Merry et al., 1997
     Nelfinavir 2250 Azithromycin 2 2 Amsden et al., 2000
     Diltiazem 30 Tacrolimus 4.3 B Hebert and Lam, 1999
     Atrovastatin 80 Digoxin 1.15 1.2 A Boyd et al., 2000
10 Digoxin 1 Boyd et al., 2000
Induction
     Rifampin 600 Fexofenadine 0.43 0.59 CLr NS NS A Hamman et al., 2001
600 Talinolol 0.65 P-gp ×4.2 A Westphal et al., 2000b
600 Tacrolimus 14→7% CLtot +47% Hebert et al., 1999
600 Digoxin 0.42 CLr NS NS P-gp ×3.5 A Greiner et al., 1999
600 Glyburide 0.78 −15% C Niemi et al., 2001
600 Glipizide −36% C Niemi et al., 2001
600 Saquinavir 0.35 Grub et al., 2001
600 Saquinavir 0.57 Grub et al., 2001
     St. John's wort Digoxin 0.82 P-gp ×1.4 A Durr et al., 2000
Digoxin 0.75 0.74 A Johne et al., 1999
Cyclosporine Trough conc. −64% Barone et al., 2000

  • BA, bioavailability; CLr, renal clearance; CLtot, total clearance; CLbile, biliary clearance; NS, not significant; M/P(AUC), the ratio of AUC of metabolites to that of parent drugs; A, involvement of P-gp is suggested to be obvious; B, the cases cannot be distinguished between involvement of P-gp and CYP3A4; C, the cases cannot discriminate among other possibilities.

  • ↵ a IC50 or Ki values in vitro are cited from Wu et al., 2000; Kim et al., 1999; Kawahara et al., 2000; Zhang and Benet, 1998; Yumoto et al., 1999; Gao et al., 2001; Tiberghien and Loor, 1996.

  • ↵ b Represents minimal and maximal values reported by several authors.