TABLE 1

In vitro EC50 values of P-gp inhibitors compared with those reported previously (Ekins et al., 2002;Rautio et al., 2006) The ratios, therapeutic Cmax/EC50 and Cmaxu/EC50, provide a rank order of the potency of the drug to produce drug interactions at the human BBB. Fraction unbound values are based on reported human data and drug package inserts. Based on the FDA guidance of 0.1 or greater therapeutic Cmax/EC50 as the screening criteria (http://www.fda.gov/cder/drug/druginteractions/decisiontree.htm#dt_pgp), all the drugs listed below, except indinavir, would be classified as potential in vivo inhibitors of P-gp. Experimental values are mean ± S.D. of at least three independent experiments.




EC50 (Mean ± S.D.)

Previous Reported EC50

Emax (Mean ± S.D.)

γ (Gamma) (Mean ± S.D.)

Therapeutic Cmax

Cmaxu

Therapeutic Cmax/EC50

Cmaxu/EC50
μM μM μM μM
Cyclosporine A 0.6 ± 0.3 0.46 ∼ 6.2 2.5 ± 0.4 2.0 ± 0.7 1.11 0.078 1.78 0.12
Quinidine 0.9 ± 0.2 2 ∼ 55 1.6 ± 0.3 0.8 ± 0.4 8.94 1.16 9.57 1.24
Quinine 1.2 ± 0.3 N.A. 1.7 ± 0.04 1.1 ± 0.3 18.8 2.44 15.2 1.97
Verapamil 3.8 ± 1.3 1.5 ∼ 61 4.3 ± 0.8 0.8 ± 0.2 0.66 0.07 0.17 0.02
Ketoconazole 2.8 ± 1.2 0.7 ∼ 29 2.9 ± 0.4 0.8 ± 0.1 8.47 0.085 2.98 0.03
Itraconazole 0.3 ± 0.2 0.5 2.0 ± 0.1 1.0 ± 0.2 0.92 0.033 2.98 0.11
HIV inhibitors
   Amprenavir 5.8 ± 0.9 >100 4.2 ± 0.7 1.1 ± 0.2 15.15 1.52 2.61 0.26
   Indinavir N.D. >50 N.D. N.D. 9.8 3.82 N.D. N.D.
   Nelfinavir 18.1 ± 8.6 1.4 ∼ 44 5.6 ± 2.0 1.0 ± 0.2 5.64 0.11 0.31 0.01
   Ritonavir 12.1 ± 5.0 3.8 4.3 ± 1.2 1.6 ± 0.4 15.26 0.31 1.26 0.03
   Saquinavir 15.9 ± 4.1 6.5 4.4 ± 1.2 1.2 ± 0.3 5.64 0.11 0.35 0.01
   Atazanavir 13.2 ± 4.8 N.A. 1.9 ± 0.1 1.5 ± 0.3 7.66 1.07 0.58 0.08
   Lopinavir 3.1 ± 0.8 N.A. 1.8 ± 0.1 0.8 ± 0.1 15.59 0.31 5.03 0.10
   Tipranavir 2.9 ± 0.9 N.A. 1.5 ± 0.3 1.0 ± 0.4 94.8 0.09 32.39 0.03
Erythromycin 44.6 ± 18 38 3.5 ± 0.6 1.5 ± 0.5 4.77 0.76 0.11 0.02
Clarithromycin
26.4 ± 10
N.A.
3.8 ± 1.2
1.1 ± 0.2
3.21
1.86
0.12
0.07
  • EC50, concentration of drug that produces half-maximal (Emax) inhibition of P-gp; γ (gamma), the Hill coefficient; Cmax, maximal therapeutic plasma (or blood) concentrations; Cmaxu, unbound Cmax; N.D., could not be determined; N.A., not available