Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice.

An 18-mer full-phosphorothioate oligonucleotide with sequence antisense to the first six codons of the open reading frame of bcl-2 (G3139) has shown efficacy against the DoHH2 lymphoma implanted in severe combined immunodeficient mice. This study evaluated the pharmacokinetics of 35S-labeled G3139 in female BALB/c mice after single i.v. bolus administration or s.c. infusion for 1 week. After 100 microg i.v. bolus (approximately 5 mg/kg), the radioactivity was rapidly distributed and eliminated, with low blood levels 6 hr after administration. Most of the initial plasma radioactivity was protein bound (98% at 5 min). Tissue to plasma ratios were 87 for kidney, 17 for liver, 5 for spleen, 2.5 for heart and lung and 3.5 for gut. High-performance liquid chromatographic determination of G3139 showed triexponential kinetics, with alpha, beta and gamma half-lives of 5 min, 37 min and 11 hr, respectively. After 106 microg/day s.c. infusion, plasma steady state was reached by day 3, when half of the radioactivity was protein bound and 66 to 86% of the radioactivity was associated with parent drug (0.9 microg/ml). The plasma half-life of elimination for G3139 was 22 hr. Tissue to plasma ratios were similar to those after i.v. bolus administration, but accumulation was observed in all organs including bone marrow, where the levels reached were in the cytotoxic range. G3139 was metabolized to at least three different products, all observed in plasma, liver and kidney. Two metabolites eluted before the parent compound and one after the parent compound. There was greater degradation in the liver 6 hr after i.v. administration than at 24 hr, 48 hr, 3 days and 7 days after s.c. administration. In the kidney, most radioactivity was G3139. All degradation products were found in the urine but only traces of parent drug were eliminated. After both routes of administration, most of the radioactivity was eliminated in the urine and to a lesser extent in the feces. Significantly more radioactivity was excreted in the urine after i.v. bolus, compared with s.c. infusion (33% on day 1 and 55% by day 3 for i.v. vs. 7.2% on day 1 and 12.9% by day 3 for s.c.). These data show that s.c. infusion resulted in less excretion and metabolism of the administered dose.