Vol. 50, Issue 3, 387-412, September 1998

Prediction of Pharmacokinetic Alterations Caused by Drug-Drug Interactions: Metabolic Interaction in the Liver

K. Ito, T. Iwatsubo, S. Kanamitsu, K. Ueda, H. Suzuki and Y. Sugiyama^a

Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

I. Introduction
II. Drug-Drug Interactions Other Than Involving Metabolism
    A. Drug-drug interactions involving plasma protein binding
    B. Drug-drug interactions at the transport carrier
III. Drug-Drug Interactions Involving Metabolism in the Liver
    A. Examples of In Vivo Drug-Drug Interactions Involving P450 Metabolism
    B. Inhibition Mechanism of Drug Metabolism by P450
    C. Inhibition Patterns of Drug Metabolism
        1. Competitive Inhibition.
        2. Noncompetitive Inhibition.
        3. Uncompetitive Inhibition.
    D. Prediction of In Vivo Drug-Drug Interactions Based on In Vitro Data
        1. General Equations.
        2. The evaluation of the unbound concentration of the inhibitor in vivo.
    E. Examples of the Prediction of Drug-Drug Interactions Based on Literature Data
        1. Successful Cases of In Vitro/In Vivo Prediction.
        2. Interactions Predictable for the Objective Metabolic Pathway but not Predictable for the Overall Data.
        3. Interactions Not Predictable by In Vitro/In Vivo Scaling.
    F. Procedure for Predicting Inhibitory Effects of Coadministered Drugs on the Hepatic Metabolism of Other Drugs
    G. Mechanism-Based Inhibition
        1. Characteristics of Mechanism-Based Inhibition.
        2. Kinetic Analysis of Mechanism-Based Inhibition: Analysis of In Vitro Data.
        3. Prediction of In Vivo Interactions from In Vitro Data in the Case of Mechanism-Based Inhibition.
    H. Problems To Be Solved for the More Precise Prediction of Drug-Drug Interactions
        1. Estimation of the Tissue Unbound Concentration of the Inhibitor That Is Actively Transported into Hepatocytes.
        2. Evaluation of Drug-Drug Interactions Involving Drug Metabolism in the Gut.
References