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

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Abstract

In recent years, there has been an increased understanding of P-glycoprotein (P-GP)-mediated pharmacokinetic interactions. In addition, its role in modifying the bioavailability of orally administered drugs via induction or inhibition has been also been demonstrated in various studies. This overview presents a background on some of the commonly documented mechanisms of multidrug resistance (MDR), reversal using modulators of MDR, followed by a discussion on the functional aspects of P-GP in the context of the pharmacokinetic interactions when multiple agents are coadministered. While adverse pharmacokinetic interactions have been documented with first and second generation MDR modulators, certain newer agents of the third generation class of compounds have been less susceptible in eliciting pharmacokinetic interactions. Although the review focuses on P-GP and the pharmacology of MDR reversal using MDR modulators, relevance of these drug transport proteins in the context of pharmacokinetic implications (drug absorption, distribution, clearance, and interactions) will also be discussed.

Section snippets

Biology of multidrug resistance

Of the approximately 1.3 million new cases of cancer each year in North America (Landis et al., 1998), a fair proportion are drug resistant (Gottesman, 1993). This is often due to the fact that these cancers either are inherently untreatable or are resistant to a wide variety of anticancer drugs or their combinations. MDR is a term used to describe the phenomenon characterized by the ability of drug resistant tumors to exhibit simultaneous resistance to a number of structurally and functionally

Absorption and distribution

The role of drug transporters in absorption of drugs has been a subject of numerous scientific contributions and is beyond the scope of the review. One potential role of membrane transporters which has been underrepresented in the past is its inducibility which may have implications in the oral bioavailability of drugs via increased clearance. Reduction in the oral bioavailability may occur as a consequence of induction of intestinal activity of membrane transport proteins, while increased

Involvement of multiple transporters in clearance of anticancer agents

It is possible that first and second generation MDR modulators may have induced pharmacokinetic interactions due to non-specific blockade of other ABC transporters other than P-GP. For example, both cyclosporin A (a first generation MDR modulator) and its non-immunosuppressive analog PSC 833 (a second generation MDR modulator) are close structural analogs that were initially developed for P-GP-mediated MDR reversal (Fig. 2). Whereas cyclosporin A inhibits both cMOAT and P-GP, it is a more

Altering specificity of MDR modulators

Certain third generation highly potent and selective modulators such as LY 335979 (Dantzig et al., 1996), OC144-093 (Newman et al., 2000), and R101933 (Van Zuylen et al., 2000) have been shown to exhibit minimal pharmacokinetic interactions with anticancer agents that are P-GP substrates. This may present a unique approach for designing MDR modulators that are less likely to elicit adverse pharmacokinetic interactions. The increased potency and specificity demonstrated by these newer agents and

Conclusions

Since the elucidation of P-GP as a membrane transport pump in mid-1970s, considerable work has been done in understanding the physiological, biochemical, and the pharmacological role of P-GP. In particular, two key pharmacological issues have surfaced in the past decade: (1) strategies to block the transport pump as a means of circumventing MDR and (2) the role of membrane transporters in modifying the pharmacokinetics of drugs. This review highlighted several examples where P-GP blockers

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