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