Renal uptake and tolerability of a 2'-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey.
The primary target organ for uptake of systemically administered phosphorothioate oligonucleotides is the kidney cortex and the proximal tubular epithelium in particular. To determine the effect of oligonucleotide uptake on renal function, a detailed renal physiology study was performed in cynomolgus monkeys treated with 10-40 mg/kg/week ISIS 113715 for 4 weeks. The concentrations of oligonucleotide in the kidney cortex ranged from 1400 to 2600 μg/g. These concentrations were associated with histologic changes in proximal tubular epithelial cells that ranged from the appearance of cytoplasmic basophilic granules to atrophic and degenerative changes at higher concentrations. However, there were no renal functional abnormalities as determined by the typical measurements of blood urea nitrogen, serum creatinine, creatinine clearance, or urine specific gravity. Nor were there changes in glomerular filtration rate, or renal blood flow. Specific urinary markers of tubular epithelial cell damage, such as N-acetyl-glucosaminidase, and α-glutathione-s-transferase were not affected. Tubular function was further evaluated by monitoring the urinary excretion of amino acids, β(2)-microglobulin, or glucose. Renal function was challenged by administering a glucose load and by examining concentrating ability after a 4-h water deprivation. Neither challenge produced any evidence of change in renal function. The only change observed was a low incidence of increased urine protein/creatinine ratio in monkeys treated with ≥40 mg/kg/week which was rapidly reversible. Collectively, these data indicate that ISIS 113715-uptake by the proximal tubular epithelium has little or no effect on renal function at concentrations of 2600 μg/g.
ISIS Pharmaceuticals, Carlsbad, CA 92010, United States. shenry@isisph.com
Scott P
SP
Henry
Mark
M
Johnson
Thomas A
TA
Zanardi
Robert
R
Fey
Diana
D
Auyeung
Patrick B
PB
Lappin
Arthur A
AA
Levin
D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood / Q000652:urine; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism*; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D008252:Macaca fascicularis; D008297:Male; D009843:Oligoribonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011506:Proteins / Q000378:metabolism; D014018:Tissue Distribution
D009843:Oligoribonucleotides; D011506:Proteins; C496122:ISIS-113715; D003404:Creatinine; D005947:Glucose