Evaluation of the effects of serial phlebotomy on the transcriptome of major tissues and on the response to toxicants in rats

Preclinical pharmacokinetic (PK) evaluations are typically conducted in rats before in vivo toxicologic evaluations. It is unclear how the serial bleeding procedures in PK studies affect tissue homeostasis or sensitivity to toxicity. In this study, our objective was to evaluate the impact of serial bleeding on the transcriptome of various major tissues (kidney, heart, liver, spleen) and their response to two well-characterized molecules, doxorubicin and cisplatin. Rats received single i.v. injections of saline, doxorubicin (8 mg/kg) or cisplatin (4 mg/kg). In each group, half of the rats were serially bled by tail vein. Serial bleeding was associated with slight decreases of red blood cell parameters, but did not result in histopathological changes or in increased sensitivity to doxorubicin and cisplatin toxicity based on clinical pathology and histopathology evaluation. In addition, serial bleeding did not induce significant gene expression changes in either vehicle- or compound-treated rats when compared to their respective control groups. Overall, these results suggest that the serial bleeding procedure used in PK studies in our institution minimally affects the tissue response to toxicants, and support the use of these studies to generate early toxicology data in drug discovery.