Dose | kaa | Cent | logPo:w | pKa | fup | Rb | Peffb | Kmc | In Vivo CLint, hd | In Vitro CLint, he | |
---|---|---|---|---|---|---|---|---|---|---|---|
mg | h−1 | μM | μm/s | μM | l/h | l/h | |||||
Atorvastatin | 40 | 3.7 | 15 | 4.07 | 4.46 | 0.051 | 0.61 | 1.72 | 33 | 1990 | 213 |
Buspirone | 20 | 5.0 | 14 | 2.63 | 7.32, 4.12 | 0.05 | 0.81 | 7.17 | 8.0 | 20,700f | 963 |
Cyclosporineg | 380 | 2.0 | 32 | 3.45 | Neutral | 0.019h | 1.36 | 3.30 | 1.4 | 1450 | 279 |
570 | 1.1 | 14 | |||||||||
Felodipine | 10 | 2.8 | 4.0 | 3.86 | Neutral | 0.0048 | 0.70 | 3.00 | 5.3 | 39,100 | 7150 |
Indinavirg | 400 | 1.8 | 57 | 2.92 | 5.9, 3.7 | 0.36 | 0.84 | 2.07i | 0.1 | 1120 | 2090 |
Lovastatin | 20 | 0.8 | 9.0 | 4.26 | Neutral | 0.017 | 0.57 | 5.05 | 7.8 | 5750f | 17,200 |
Midazolam | 3 | 4.2 | 2.2 | 3.25 | 6.1 | 0.031 | 0.55 | 6.73 | 3.3 | 1610 | 1540 |
Nisoldipine | 20 | 3.0 | 8.6 | 3.80 | Neutral | 0.0041 | 1.0 | 4.05 | 2.1 | 38,900 | 25,200 |
Saquinavirg | 600 | 2.5 | 37 | 4.10 | 8.2 | 0.028 | 0.74 | 3.33i | 0.3 | 7660f | 26,800 |
Simvastatin | 40 | 2.0 | 10 | 4.71 | Neutral | 0.014 | 0.57 | 4.30 | 3.4 | 14,300f | 25,500 |
Tacrolimus | 0.05 mg/kg | 2.6 | 0.7 | 3.26 | Neutral | 0.013h | 35 | 5.95i | 2.6 | 7530 | 3750 |
Terfenadine | 120 | 2.8 | 47 | 5.62 | 9.7 | 0.03 | 1.0 | 5.43i | 1.0 | 70,600 | 12,400 |
logPo:w, partitioning coefficient between octanol and water; Papp(A-B), apparent permeability (apical-basolateral).
a Estimation of ka was based on clinical data using
b Estimated from Papp(A-B) data in MDCK-MDR1 cells (Gertz et al., 2010); for cyclosporine, in vivo Peff data were used (Supplemental Table 1).
c Represent the unbound Km values (if original studies reported microsomal protein concentration).
d Values reported in Gertz et al. (2010); updated fup values for atorvastatin, cyclosporine, felodipine, lovastatin, nisoldipine, simvastatin, and tacrolimus in comparison to Gertz et al. (2010).
e Data represent means from three human liver microsome pools (Gertz et al., 2010).
f In vivo intrinsic clearance was estimated from oral data; for buspirone intravenous clearance exceeded hepatic blood flow and showed very large interindividual variability (Gammans et al., 1986).
g Fraction absorbed of cyclosporine (Neoral and Sandimmune, 0.9 and 0.5, respectively), indinavir, and saquinavir (Invirase) 0.8 and 0.3, respectively.
h Based on equilibrium dialysis experiments in stainless steel chambers.
i Based on Papp(A-B) data in the presence of a P-glycoprotein inhibitor.