Mechanism of altered vectoral hepatic excretion

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DESCRIPTION (provided by applicant): Understanding drug absorption, distribution, metabolism, and excretion (ADME) is essential for the development of safe, effective drug therapies. Moreover, understanding mechanisms by which drug-drug interactions affect drug ADME is also critical for identifying potential toxicities or side effects of pharmaceutical preparations. Specifically, this work seeks to relate the effects of microsomal inducers on hepatic excretion of drug conjugates to regulation of hepatic drug transporters responsible for the excretion of drug conjugates that result from phase I and II metabolism. This work will determine whether alteration in the vectoral route of excretion of acetaminophen (APAP) metabolites from hepatobiliary to hepatovascular by pretreatment with Phenobarbital-type microsomal inducers is due to changes in hepatic levels of the organic anion transporters mrp2 and mrp3. Therefore, specific aims 1 and 2 will determine whether hepatic levels/and or distribution of mrp2 and/or mrp3 is altered following treatment with constitutive active receptor (CAR) inducers and if these changes correlate with increased excretion of APAP-glucuronide, APAP-sulfate, and APAP-GSH from the liver into the blood. Next, specific aim3 will determine whether APAP metabolites are substrates for mrp2 and mrp3 using membrane vesicles prepared from Sf9 cells that heterologously express mrp2 or mrp3. Lastly, specific aim 3 will determine whether PB increases mrp3 mRNA through nuclear translocation of CAR and activation of a putative PB response element in the promoter region for rat mrp3. These studies will elucidate mechanisms that control hepatic transport and excretion of pharmaceuticals and will aid in the development of safer more biologically effective drug preparations.