Does P-glycoprotein play a role in anticancer drug pharmacokinetics?
The multidrug-resistance P-glycoprotein is a drug efflux transport protein abundantly present in various types of human cancer. The protein is encoded by the MDR1 gene and its function is sensitive to modulation by competitive inhibition. Clinical studies have indicated that inhibitors of P-glycoprotein function dramatically decrease the systemic clearance of anticancer agents, necessitating dose reduction. This dose reduction not only complicated the interpretation of toxicity and response data, but also presented a serious obstacle in the development and rational use of P-glycoprotein inhibitors. It is now evident that the pharmacokinetic interference between anticancer drugs and P-glycoprotein inhibitors is due primarily to competition for drug metabolizing enzymes. A wealth of recent experimental data shows that many of the previously tested P-glycoprotein inhibitors, including verapamil, cyclosporin A, and valspodar (SDZ PSC 833), are substrates and/or potent inhibitors of cytochrome P450 3A4 (CYP3A4). Future development and clinical use of potent P-glycoprotein modulators lacking high affinity for CYP3A4 should decrease the impact of these important drug interactions and will eventually result in improved therapeutic specificity and efficacy. Copyright 2000 Harcourt Publishers Ltd.
Sparreboom
Alex
A
Department of Medical Oncology, Rotterdam Cancer Institute and University Hospital Rotterdam, Rotterdam, The Netherlands
Nooter
Kees
K