Multidrug resistance (MDR) in cancer - Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs

In recent years, there has been an increased understanding of P-glycoprotei n (P-GP)-mediated pharmacokinetic interactions. In addition, its role in mo difying the bioavailability of orally administered drugs via induction or i nhibition has been also been demonstrated in various studies. This overview presents a background on some of the commonly documented mechanisms of mul tidrug resistance (MDR), reversal using modulators of MDR, followed by a di scussion on the functional aspects of P-GP in the context of the pharmacoki netic interactions when multiple agents are coadministered. While adverse p harmacokinetic interactions have been documented with first and second gene ration MDR modulators, certain newer agents of the third generation class o f compounds have been less susceptible in eliciting pharmacokinetic interac tions. Although the review focuses on P-GP and the pharmacology of MDR reve rsal using MDR modulators, relevance of these drug transport proteins in th e context of pharmacokinetic implications (drug absorption, distribution, c learance, and interactions) will also be discussed. (C) 2000 Elsevier Scien ce B.V. All rights reserved.