Rz. Yu et al., Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate oligonucleotide targeting human Ha-ras mRNA in mouse and monkey, J PHARM SCI, 90(2), 2001, pp. 182-193
The plasma pharmacokinetics and tissue disposition of ISIS 2503 were studie
d in mice following single and multiple bolus intravenous (iv) injections o
f 1-50 mg/kg, and in monkeys following single and multiple 2-h iv infusions
of 1-10 mg/kg and bolus iv injections of 1 mg/kg of ISIS 2503. ISIS 2503 a
nd its metabolites were measured in plasma, urine, and tissues using solid-
phase extraction followed by capillary gel electrophoresis (CGE). In both s
pecies, the plasma clearance of ISIS 2503 was characterized by rapid distri
bution to tissues, and to a lesser extent, metabolism. The plasma clearance
in mice was at least two-fold more rapid than in monkeys at equivalent dos
es. The plasma disposition (t(1/2)) increased with dose. The highest concen
trations of oligonucleotide were consistently observed in the kidney and li
ver in both species. At equivalent doses, tissue concentrations in monkeys
were much higher than tissue concentrations in mice. Urinary excretion of t
otal oligonucleotide was a minor elimination pathway in both species at dos
es < 10 mg/kg. However, urinary excretion of total oligonucleotide in mice
was increased to 12-29% as dose increased from 20 to 50 mg/kg. (C) 2001 Wil
ey-Liss, Inc.