Necropsy & Tissues from Control and high dose rats
SIGNALMENT: 10 week old, female Wistar (Crl: (WI)BR) rats
4-week gavage safety study of the R-enantiomer & the S-enantiomer of Compound X, a subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist for treatment of Parkinson’s disease.
3 dose levels, organ weights, complete clinical pathology & necropsy, limited tissue list for histopathology.
GROSS PATHOLOGY/ ORGAN WEIGHTS: Kidneys had no gross abnormalities.
Statistically significant increases in mean kidney weights occurred for mid dose rats with either enantiomer (21% with R-enantiomer and 16% with S-enantiomer) and for high dose rats with the S-enantiomer (35%).
LABORATORY RESULTS: Urinalysis: Increased urinary protein (³100 mg/dL) occurred at mid and high doses with both enantiomers.
MORPHOLOGIC DIAGNOSIS AND ETIOLOGY: Renal tubular hypertrophy due to drug-induced enzyme induction.
Diffuse renal tubular hypertrophy was present in 1 of 5 mid dose and all high dose rats given the R-enantiomer and all mid and high dose rats given the S-enantiomer. This change correlated with the increased kidney weights. The degree of renal tubular hypertrophy was more pronounced with the S-enantiomer.
Ultrastructural examination of renal tubular epithelial cells from one high dose rat given the S-enantiomer showed substantial increases in rough endoplasmic reticulum (RER) correlating with tubular hypertrophy.
A puzzling aspect of these investigations is that Compound X (the racemic mixture) caused increased kidney weights in previous studies without corresponding morphological alterations including tubular hypertrophy. In the 4-week study with the racemic mixture, mean kidney weight was increased 21% at the mid dose and 41% at the high dose. Urinary proteins were also increased at the high dose. 4 weeks following drug withdrawal, kidney weights remained increased (20-22%) for females of the mid and high dose reversal groups. Diffuse renal tubular hypertrophy was not apparent microscopically until individual enantiomers of the compound were administered to rats. The microscopic and ultrastructural findings in treated rats are consistent with enzyme induction in the renal tubular epithelial cells. Xenobiotic metabolizing enzymes are present in the kidney as well as in liver. Diffuse renal hypertrophy secondary to enzyme induction is much less common than hepatocellular hypertrophy secondary to enzyme induction.
In a 2-week study in rats with the racemic mixture of Compound X, liver biochemistry parameters indicated slight induction of liver CYP1A and CYP3A (88-114%), and pronounced induction of UDP-glucuronyl transferase activity (UDPGT) (1.6-fold) with associated increases in liver weight. Enzyme induction was not assessed for the kidney. In the present study, hepatocellular hypertrophy was seen with both enantiomers.
Hard GC, Alden CL, et al. Non-proliferative lesions of the kidney and lower urinary tract in the rat, URG-1. In: Guides for Toxicologic Pathology, STP/ARP/AFIP, Washington, DC. 1999.
Lock EA, Reed CJ. Xenobiotic metabolizing enzymes of the kidney. Toxicol Pathol 26;18-25, 1998.
Fig 1: Kidneys from A.) Control female B.) High dose female rat treated with the test compound. H&E 20x.
Fig 2: Kidneys from A.) Control female B.) High dose female rat treated with the test compound. H&E 40x.
Fig 3: Transmission electron micrograph of renal tubular epithelial cell from one high dose rat treated with the test compound. Magnification x2850
Fig 4: Transmission electron micrograph of renal tubular epithelial cell from one high dose rat treated with the test compound. Magnification x3800.