Predicting the hepatic clearance of xenobiotics in humans from in vitro data

Values for V_max and K_m determined during the in vitro metabolism of a xenobiotic to a known metabolite by a specific human isozyme of cytochrome P450 (P450) were used to predict the hepatic clearance (CL_H) of the xenobiotic to that metabolite. The calculated CL_H values were then compared to literature values of clearance (CL) to the same metabolite obtained during pharmacokinetic studies in humans. For the 6-hydroxylation of chlorzoxazone (P450 2E1) the predicted and actual clearances were 110±77 mL min^?1 and 110 mL min^?1, respectively. For the 6β-hydroxylation of cortisol, the deethylation of lidocaine (two studies), and the oxidation of nifedipine (all P450 3A3/4) the values were 13±15 mL min^?1 and 13 mL min^?1; 758±282 or 829±283 mL min^?1 and 875 mL min^?1; and 284±176 mL min^?1 and 294 mL min^?1, respectively. An increase to 72±25 mL min^?1 in the CL_H of cortisol to 6β-hydroxycortisol was calculated following rifampicin treatment. Finally, the polymorphic nature of the metabolism (P450 2D6) of mexiletine was confirmed. The usefulness of the method and its limitations are discussed.