Effects of microsampling on toxicity assessment of hematotoxic compounds in a general toxicity study in rats.

Microsampling (MS) has been increasingly used in toxicity studies reducing animal use for toxicokinetic analysis. However, especially for drugs with hematotoxic properties, the potential effects of MS on hematological parameters and subsequent toxicity assessment should be considered, while such properties are frequently unknown at the discovery stage. Here, we conducted a rat 2-week study of hematotoxic compounds and evaluated the effects of MS on toxicity assessment. Six-week-old female SD rats were orally dosed with vehicle, methylene blue trihydrate (MB: 300 mg/kg/day), or azathioprine (AZP: 12 and 24 mg/kg/day) for 2 weeks. Each treatment group was divided into non-MS and MS subgroups, and in the MS subgroups, 50 µL/time point of blood was collected from the jugular vein at 7 time points each on Days 1 and 13 of dosing. The test items included clinical signs, body weight, urinalysis, hematology, blood chemistry, necropsy, organ weight, and histopathology. In the MB non-MS subgroup, there were low values in red blood cell parameters, high values in reticulocytes and bilirubin, and increased extramedullary hematopoiesis, reflecting hemolytic anemia. In the AZP non-MS subgroup, there were low values of red and white blood cell parameters and decreased cellularity in the bone marrow, reflecting myelosuppression. The effects of MB and AZP were similarly observed in the MS subgroups, and the effects of MS on the toxicological endpoints were generally small. Based on these results, the effects of MS on toxicity assessment were considered to be small in rat toxicity studies even for hematotoxic compounds.

Effect of food thickener and jelly wafer on the pharmacokinetics of levofloxacin orally disintegrating tablets.

This study was designed to determine the effects of a food thickener and deglutition aid jelly for oral administration, jelly wafer, on the pharmacokinetics of levofloxacin orally disintegrating tablets. With an increase in immersion time, the disintegration time of levofloxacin orally disintegrating tablets immersed in food thickener was prolonged, whereas that of the tablets immersed in jelly wafer was shortened. The dissolution behavior of non-immersed levofloxacin orally disintegrating tablets was not similar to that of tablets immersed in food thickener, but was similar to that of tablets immersed in jelly wafer. The time to reach the maximum systemic levofloxacin concentration was the same for non-immersed orally disintegrating tablets and tablets immersed in food thickener and jelly wafer. Moreover, there was no significant difference in the maximum concentration after administration between non-immersed orally disintegrating tablets and tablets immersed in food thickener or jelly wafer. These findings suggest that drugs with a high bioavailability, such as levofloxacin, enter the systemic circulation even when administered with a food thickener or jelly wafer.