Beyond the Michaelis-Menten: Accurate Prediction of In Vivo Hepatic Clearance for Drugs With Low KM

Abstract

Clearance (CL) is the major pharmacokinetic parameter for evaluating systemic exposure of drugs in the body and, thus, for developing new drugs. To predict in vivo CL, the ratio between the maximal rate of metabolism and Michaelis-Menten constant (V_max /K_M estimated from in vitro metabolism study has been widely used. This canonical approach is based on the Michaelis-Menten equation, which is valid only when the K_M value of a drug is much higher than the hepatic concentration of the enzymes, especially cytochrome P450, involved in its metabolism. Here, we find that such a condition does not hold for many drugs with low K_M , and, thus, the canonical approach leads to considerable error. Importantly, we propose an alternative approach, which incorporates the saturation of drug metabolism when concentration of the enzymes is not sufficiently lower than K_M . This new approach dramatically improves the accuracy of prediction for in vivo CL of high-affinity drugs with low K_M . This indicates that the proposed approach in this study, rather than the canonical approach, should be used to predict in vivo hepatic CL for high-affinity drugs, such as midazolam and propafenone.