LBOVI-A-2Using PharmGenix™ rats to detect tacrine hepatotoxicity

Abstract

BACKGROUND/AIMS Over 90% of drug candidates fail in clinical trials, incurring high costs to the pharmaceutical industry. To address this problem, PhysioGenix has developed a novel combinatorial breeding strategy, the PharmGenix™ panel, to capture greater genetic diversity within the rat genome and allow for preclinical drug screening. Tacrine, which causes hepatotoxicity in a small percentage of the human population, was tested to demonstrate the utility of this panel. METHODS A single dose of tacrine (35 mg/kg) was administered to each of six hybrid PharmGenix™ strains, CD‐IGS and CDF strains. Rats were euthanized twenty‐four hours later and serum analyzed for alanine transaminase (ALT) and aspartate transaminase (AST) levels, indicators of hepatotoxicity. RESULTS Tacrine did not significantly elevate ALT levels in CD‐IGS or CDF, however, the PharmGenix™ panel showed significant ALT elevations in five of the six strains, ranging from 111% to 142% of control values. CD‐IGS and CDF exhibited increases in AST levels of 82% and 174%, respectively, while the PharmGenix ™ rats showed much higher AST levels, ranging between 621% and 1069% of control values in four of the six strains. CONCLUSIONS The ability to detect significant AST and ALT elevations in the PharmGenix™ panel, but not in CD‐IGS or CDF, suggests a genetic component underlies the development of tacrine toxicity and may have alerted the pharmaceutical industry to toxicity currently seen in a small percentage of the human population. Clinical Pharmacology & Therapeutics (2005) 79, P82–P82; doi: