Abstract
The belated discovery of drug toxicity after
successful preclinical trials plagues the pharmaceutical industry. We believe that a major reason for this
failure is that researchers often neglect the role genetics plays in predicting
drug toxicity in model systems. Current
rodent models typically lack genetic diversity, have variable phenotypic
responses, or cannot be reliably produced.
To address this, PharmGenix™ rat panels
(each comprised of six F1 strains) were created using a novel combinatorial
breeding strategy. These PharmGeni™ rats are the first genetically diverse
system that can faithfully recapitulate a heterozygous test population in a
controlled fashion. PharmGenix™
panels capture over 80% of the genetic diversity found in the rat genome and
enable drug responses to different genome backgrounds to be tested
simultaneously. PharmGenix™
rats were tested for their sensitivity to the toxic effects of gentamicin, methapyrilene, and tacrine. Following
drug treatment, biomarkers in the urine and blood were analyzed and organ
pathology was assessed. Gentamicin caused elevations in BUN and creatinine in two
of the PharmGenix™ strains. F344 rats also responded to gentamicin, but it was only the
differential response exhibited by the PharmGenix™
panel that revealed that genetic components underlie the toxic response. After methapyrilene
treatment, most of the strains exhibited elevations in ALT and AST. However, several of the PharmGenix™
hybrids were more sensitive than either CD-IGS or F344 in detecting
toxicity. Tacrine
led to elevated ALT and AST levels in three of the PharmGenix™
strains but not in the industry-standard CD-IGS or F344 strains. Abnormal clinical chemistries were accompanied
by histopathological changes in the kidney (gentamicin) and liver (methapyrilene). These results underscore the need to consider
the influence of genetic components when evaluating new drugs in preclinical
studies. Researchers who discover a
differential toxic response among PharmGenix™
strains will use this information as a starting point for drug optimization,
drug rescue, and mechanistic studies.
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