Two Week Oral Dose Range-Finding Toxicity Study of WR269410 in Rats
Abstract
This study evaluated the toxicity of WR269410 in rats following two weeks of daily oral administration by gavage. Dose levels studied were 0 (vehicle control), 2.0, 6.0, and 18.0 mg/kg/day at study initiation. On Day 7, the mid dose level (6.0 mg/kg/day) was elevated above the high dose to 30 mg/kg/day for the second treatment week due to a lack of significant toxicity at the high dose during the first week of treatment The primary toxic effect of WR269410 was hemolytic anemia, which was supported by macrocytosis, reticulocytosis, Heinz bodies, splenomegaly and extramedullary hematopoiesis. Females were more sensitive than males to the anemic state. Anemia was seen in males at the two higher doses, but was apparent in all female treatment groups. Methemoglobinemia, the expected pharmacologic effect, was also observed at all three dose levels. As this is the desired pharmacologic effect of WR269410, its occurrence was not considered indicative of toxicity. Cardiomegaly, possibly secondary to the methemoglobinemic and anemic state, was seen only in females at 6.0/30.0 mg/kg/day. The purpose of this study was to select dose levels for a three month toxicity study in rats. It is anticipated that significant toxicity would occur at the high dose, marginal or no toxicity would be observed at the mid dose, and no toxicity would occur at the low dose level. On this basis, the following dose levels are suggested: 0, 1, 2.5 and 6 mg/kg/day. After consultation with the Sponsor, the following dose levels have been chosen for the three month toxicity study in rats: 0, 1, 3, and 10 mg/kg/day.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 09, 1993
- Accession Number
- ADA573985
Entities
People
- Barry S. Levine
- Clyde W. Wheeler
- Michael J. Tomlinson
Organizations
- University of Illinois at Chicago