Abstract
An animal system that predicts genetic components of drug toxicity has been
developed by PhysioGenix. The system,
termed the PharmGenix™ panel, comprises six F1
hybrid strains combinatorially bred from four inbred parental strains. Combinatorial breeding enables different
genome backgrounds to be tested in a controlled fashion. The four parental strains were selected for
genetic diversity at various cytochrome P450 enzymes and for known phenotypic
responses to toxicants. The PharmGenix™ panel emulates the genetic diversity and
heterogeneous genome background found within the human population, while
minimizing the number of animals required to detect drug toxicity. Because the individuals from each strain are
isogenic, the phenotypic consistency expected from inbred animals is maintained
in the panel throughout testing. Using a
standard ADMET study design, PharmGenix™ rats,
inbred Fischer 344 (F344) rats, and outbred CD‑IGS rats were tested for
toxic responses to the nephrotoxin gentamicin and to the hepatotoxin methapyrilene. Following drug treatment, standard clinical
chemistry analysis was used to assay biomarkers in the urine and blood. Organ pathology was assessed by histology and
biochemical analysis. After gentamicin treatment, F344, CD-IGS, and five of the six PharmGenix™ strains showed a two- to four-fold
elevation in blood urea nitrogen and creatinine compared to vehicle controls
while one of the PharmGenix™ strains was
resistant. Following methapyrilene
treatment, all of the strains exhibited elevations in alanine transaminase,
aspartate transaminase, and alkaline phosphatase. However, two of the PharmGenix™
hybrids were more sensitive than either CD-IGS or F344 in detecting methapyrilene toxicity.
Abnormal clinical chemistries were accompanied by pathological changes
found in the kidney (gentamicin) and liver (methapyrilene).
Statistical analysis of clinical chemistries using the Mantel-Haenszel test shows that the PharmGenix™
panel has more power to detect toxic responses than either CD‑IGS or F344
rats. In addition, the differential
responses of the PharmGenix™ strains to these
two compounds demonstrates that the PharmGenix™
panel is capable of revealing genetic components that underlie the toxic
response to these drugs. Importantly,
our data shows that some PharmGenix™
strains may be more sensitive to drugs than their inbred parent strains. These results emphasize the importance of
testing the contribution of genome backgrounds when evaluating new drug
compounds in animals. Ultimately, PhysioGenix’s combinatorial rat panels will enable
faster and more sensitive detection of drug toxicity and efficacy to meet the
discovery and preclinical needs of the pharmaceutical industry.
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