Kinetic and molecular analyses of drug-drug interactions

In normal clinical drug therapy, some drugs are often concomitantly prescribed rather than used as monotherapy. Consequently, an unexpected reduction in pharmacological effects and/or side effects is sometimes observed in some of patients due to drug-drug interactions. In particular, we have focused on the pharmacokinetic interaction, which occurs in determinant molecules (metabolic enzymes and transporters) involving the time-profile of drug concentrations at the target sites (receptors) and we have established experimental systems to quantitatively predict in vivo drug-drug interactions from in vitro experiments (Fig. 5).
Among the drug interactions caused by metabolic enzymes, competitive and non-competitive inhibition of CYP (cytochrome P450) enzymes, which mainly catalyze phase-I oxidative reactions, have been extensively studied. Moreover, we have also investigated other cases where drugs, such as rifampicin and phenobarbital, which can induce the expression of metabolic enzymes, increase the metabolism of co-administered drugs and some metabolic products covalently bind to metabolic enzymes and irreversibly inhibit their metabolism (mechanism-based inhibition).
To explain several forms of drug interactions quantitatively, we have proposed various kinds of mathematical models and demonstrated that we can predict a change in the in vivo plasma concentration profiles by using kinetic parameters obtained from in vitro experiments. Our prediction methods for drug interactions that avoid false negative predictions have been adopted in the guideline from the Japanese Ministry of Health, Labour and Welfare and are now widely used in the field of drug discovery and development.
Since the history of transporter research is shorter than that of metabolic enzymes, we are carrying out detailed investigations of drug interactions mediated by transporters. In this laboratory, we were the first to demonstrate that the drug interaction between cyclosporin A and cerivastatin can be quantitatively explained by the action of a hepatic uptake transporter (OATP2) from the results of both in vitro and in vivo experiments. This finding, showing that we must pay attention to transporter-mediated drug interactions, has had a major impact in the field of the pharmaceutical sciences. Now we are carrying out research integrating molecular biological approaches and kinetic considerations to propose a prediction method for preventing the severe side effects during the drug development stage and subsequent clinical use.

Fig. 5