Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer drugs?

Agents (modulators) that reverse the in vitro resistance of tumor cells to anticancer drugs that are substrates for P-glycoprotein (Pgp, the product of the MDR1 gene) have been given to patients concurrently with anticancer drugs in an attempt to improve therapeutic response. The vast majority of investigations into these drugs indicate that Pgp modulators decrease the systemic clearance of anticancer drugs, thus potentially nonselectively increasing exposure to normal and malignant cells and thereby potentially increasing the severity and/or incidence of adverse effects associated with the anticancer therapy. Mechanisms by which Pgp modulators could alter the pharmacokinetics of the anticancer agent include competition for cytochrome P450 intestinal or liver metabolism, inhibition of Pgp-mediated biliary excretion or intestinal transport, or inhibition of renal elimination. It is suggested that administration of Pgp modulators is unlikely to improve the therapeutic index for anticancer drugs unless agents that lack significant pharmacokinetic interactions are found. Moreover, it will likely be required that there be some cancer-tissue selectivity for modulators in order to avoid collaterally increasing the sensitivity of normal Pgp-expressing tissues to the anticancer drug.