Considerations in the design and development of transport inhibitors as adjuncts to drug therapy.
With the realization of the importance of drug efflux transporters in disease processes and treatment, development of inhibitors to these transporters has been sought for use as adjuncts to therapy. To date, inhibitors that have been best studied are modulators of P-glycoprotein, a transporter important in the removal of anticancer agents from cells and overexpression of this transporter results in multidrug resistance. There is a delicate balance between efficacy and toxicity. This review summarizes key learning points in the development of P-glycoprotein inhibitors. Topics covered include specificity of the inhibitor for the target transporter, effect on metabolism of coadministered drugs, pharmacokinetic interactions, toxicity and the salient features needed for efficacy. These points will have general application to the development of inhibitors of transporters.
Dantzig
Anne H
AH
Cancer Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. dantzig@lilly.com
de Alwis
Dinesh P
DP
Burgess
Michael
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D015195:Drug Design; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009928:Organ Specificity; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations