Modulation of Human MDR1 Function In Vivo

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Membrane transporters are increasingly recognized to be important in drug disposition. For example, the efflux transporter MDR1 (P-glycoprotein) impairs oral absorption, limits distribution into certain tissues - pharmacologic sanctuary sites - and enhances excretion via the liver, kidney and intestinal tract. Accordingly, modulation of MDR1 function by either inhibition or induction can, in principle, significantly alter a drug?s disposition and its pharmacological effect. However, supportive evidence for such changes in humans and, more importantly, their application to beneficially alter drug responsiveness is currently limited. In the case of MDR1 inhibition, the limitation has been the lack of an appropriate potent and selective drug for this purpose. This Project proposes to use a drug with these necessary characteristics as a tool to investigate the consequences and therapeutic potential of MDR1 inhibition in humans. Specific Aim 1 proposes to test the hypothesis that inhibition of MDR1 function affects target tissue availability and drug responsiveness, especially at a pharmacologic sanctuary site such as the brain. This will be accomplished by the use of a probe, wherein MDR1 inhibition would be expected to change it from a centrally ineffective drug into one with efficacy. By contrast, Specific Aim 2 focuses on the effect of MDR1 inhibition on systemic drug availability. Studies are proposed with digoxin and fexofenadine - two drugs that are essentially excreted unchanged and whose disposition appears to be MDR1-dependent. Accordingly, they may serve as in vivo probes for the transporter if such a role is validated. Because of the overlap between MDR1 substrates/inhibitors and those of cytochrome P4503A (CYP3A), studies are also proposed to investigate the selectivity of inhibition of the transporter using midazolam and the erythromycin breath test as in vivo probes of CYP3A. Additional studies will also define the relative contribution of MDR1 and CYP3A in the disposition of drugs like cyclosporine-A and erythromycin, which are substrates of both proteins.