Figure 2.

${\text{CL}}_{\text{int}}^{\text{liver}}$ predicted with the canonical approach and the new approach. (a) The canonical approach (Eq. 5) predicts an unlimited increase of ${\text{CL}}_{\text{int}}^{\text{liver}}$ as enzyme concentration increases. On the other hand, the new approach (Eq. 7) predicts the saturation of ${\text{CL}}_{\text{int}}^{\text{liver}}.$ Unless $E_{\mathrm{T}}/K_{\mathrm{M}}<0.1$ , which is highlighted by the arrow, the two approaches lead to different predictions for ${\text{CL}}_{\text{int}}^{\text{liver}}.$ (b) The canonical approach predicts considerably larger ${\text{CL}}_{\text{int}}^{\text{liver}}$ than the new approach for drugs whose $K_{\mathrm{M}}$ is not 10‐fold higher than their major metabolizing CYP concentration in the liver (Table 1 ): Pa, paclitaxel; Cy, cyclosporine; Fe, felodipine; In, indinavir; Ca, cabazitaxel; Mi, midazolam; Va, valspodar; Do, docetaxel; Co, coumarin; Sa, saquinavir; Pr, propafenone. See Table 1 for the detailed calculation of ${\text{CL}}_{\text{int}}^{\text{liver}}$ . See Methods for the detailed description of drug selection. ${\text{CL}}_{\text{int}}^{\text{liver}}$ , intrinsic clearance of the liver; V _max, maximal rate of metabolism; K _M, Michaelis‐Menten constant.; E _T, total enzyme concetnration.