MDR expression in normal tissues. Pharmacologic implications for the clinical use of P-glycoprotein inhibitors.

The use of drugs such as calcium channel blocker agents and cyclosporins as an approach to reverse the MDR phenomenon in controlled clinical trials has demonstrated the combination of these agents to markedly alter the pharmacokinetics of a number of cytotoxins associated with MDR characteristics, including doxorubicin, etoposide, paclitaxel, and vincristine. These effects are likely to be the combined effects of MDR modulators to produce decreased metabolism of the cytotoxins via the cytochrome P-450 system and decreased biliary and renal transport/excretion. It still remains to be established if the mdr1 gene is a primary drug transporter in these organs. Specificity of MDR modulators for drug metabolism and excretion requires further study, because some modulators of MDR, such as progesterone, have shown no interaction with cytotoxins (that is, doxorubicin) in clinical trials. Trials to date have indicated many modulators of MDR at doses which achieve concentrations that reverse MDR in vitro may lead to alterations of tissue function and enhance toxicity to normal tissue. In vitro data suggest many MDR modulators will enhance hematologic toxicity, beyond that predicted by the increased exposure from pharmacokinetic effects. When these interactions occur, it has been necessary to reduce the dosages of the cytotoxins in the range of 40% to 50% in most trials, if similar normal tissue toxicity--that is, myelosuppression or neuropathy--is expected. However, these empiric dose modifications in the absence of concurrent pharmacokinetic monitoring could compromise tumor exposure. Other toxicities that may be enhanced during the use of MDR modulators are nausea and vomiting, consistent with the hypothesis for a disruption of blood-brain barrier function, and augmented vinca alkaloid-associated autonomic and peripheral neuropathies. Future laboratory studies should define more effective modulators and the role of the mdr1 gene in normal tissue toxicology. These trials should focus on defining the pharmacokinetic and toxicologic interactions between the modulators and antineoplastic agents and formulate dosing guidelines for their testing in pivotal phase II and controlled phase III trials.