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-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.
Krishna
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Department of Advanced Therapeutics, British Columbia Cancer Agency, BC V5Z 4E6, Vancouver, Canada. rajesh.krishna@bms.com
Mayer
L D
LD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004337:Drug Carriers; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D004337:Drug Carriers; D014700:Verapamil; D005978:Glutathione; C070272:valspodar