Canine model for assessing CNS access P-gp substrates

Washington State University, Pullman WA

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Abstract

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to validate a P-glycoprotein (P-gp) deficient canine model [MDR1(mut/mut)] for delineating the role of P-gp in restricting access of therapeutic agents to the central nervous system (CNS). Effective delivery of CNS-active pharmaceutical agents to the brain represents a critically important therapeutic problem in many brain disorders. In particular, P-gp-mediated efflux of a variety of drugs is considered a major hindrance to effective treatment for many brain disorders including AIDS dementia complex, epilepsy, psychosis, and others. For example, all currently available HIV-1 protease inhibitors are substrates for P-gp, and are therefore actively extruded from the CNS by P-gp, rendering them ineffective for suppressing viral replication there. Furthermore, recent evidence suggests that P-gp-mediated efflux of anticonvulsant drugs from epileptic foci is a major cause of refractory epilepsy. A better understanding of the impact of P-gp-mediated efflux transport on the pharmacokinetics and pharmacodynamics of substrate drugs acting in the CNS is needed to improve the science of drug delivery to the brain. The influence of P-gp on the ratio of substrate drug concentrations in plasma, cerebrospinal fluid (CSF) and brain parenchyma represents a significant knowledge gap in the current understanding of CNS distribution of substrate drugs. Studies to further define and eventually overcome P-gp-mediated efflux of substrate drugs are hampered by lack of an appropriate biological model. The naturally-occurring, MDR1(mut/mut) canine model described in this proposal is superior to cell culture systems and the mdr1a(-/- ) knockout mouse model for dissecting the role of P-gp in CSF and brain penetration of P-gp substrates. In particular, CSF can be sampled at several time points after drug administration to determine the distribution kinetics of substrate drugs in CSF and, ultimately, brain parenchyma. The experiments outlined in this proposal will test the hypothesis that concentrations of the P-gp substrate 99mTc-sestamibi in brain and CSF, are greater in MDR1(mut/mut) dogs than in MDR1 wildtype dogs. Once this premise is established, future research can be directed at using this model to define the pharmacokinetic relationship of substrate in plasma, CSF, and brain parenchyma, to delineate the role of P-gp in those pharmacokinetic relationships, and to enhance CNS delivery of therapeutic agents. Furthermore, non-invasive imaging techniques such as gamma scintigraphy, MRI, and PET scanning may be used to more accurately assess brain parenchyma! concentrations of labeled drug, and even define drug distribution patterns within the brain in a larger animal model such as the dog.