Effects of serial cervical or tail blood sampling on toxicity and toxicokinetic evaluation in rats

To assess the influences of blood sampling volumes or sites on toxicological and toxicokinetic (TK) evaluations, 4-week duration animal studies and a single-dose TK study of imipramine were conducted. In the toxicological evaluation, six-week-old Sprague-Dawley rats were divided into no blood and blood sampling groups. Fifty microliters (microsampling) or 100 μL (larger sampling) of blood/time point was collected from the jugular vein (50 μL of data was reported previously as Yokoyama et al., 2020) or the tail vein 6 to 7 times on days 1/2 and in week 4. Although no parameters were affected by the 100 μL sample from the tail vein, the 100 μL jugular vein sampling decreased the red blood cell parameters in females, possibly due to hemorrhage at the sampling site. Regarding the TK assessment, 50 μL of blood/site/time point was collected at 6 time points from the tail and jugular vein of the same male rats after single oral administration of 10 or 100 mg/kg imipramine, which was selected as a representative drug with high distribution volume. Although there were no differences in the AUC_0-24hr and C_max values between the sites, the plasma concentrations at the early time points were significantly lower from the tail vein than the jugular vein. From our studies, 50 μL of jugular and tail vein microsampling did not affect the toxicity parameters or AUC/C_max. However, appropriate toxicity considerations and/or selection of the blood sampling site may be important in the case of larger sampling volumes or blood concentration assessment.