COMPARATIVE PHARMACOKINETICS, TISSUE DISTRIBUTION, AND TUMOR ACCUMULATION OF PHOSPHOROTHIOATE, PHOSPHORODITHIOATE, AND METHYLPHOSPHONATE OLIGONUCLEOTIDES IN NUDE-MICE

The goals of this study were to systematically compare the pharmacokin etics and tissue distribution of phosphorothioate (PS), methylphosphon ate (MP), and phosphorodithioate (PS2) oligonucleotide analogs; 15-mer s of sequence d-TAC GCC AAC AGC TCC (5'-3') complementary to the AUG r egion of K-ras were radiolabeled with carbon-14. Oligomers were admini stered as a single dose in the tail vein of nude mice harboring a K-ra s-dependent human pancreatic turner (CFPAC1). The kinetics of PS, PS2, and MP oligomer availability in the bloodstream was followed, Concent ration versus time profiles for all oligomers were biphasic, indicativ e of a two-compartment model. A rapid distribution phase with t(1/2)al pha values of 1 minute or less and an elimination phase with average t (1/2)beta values of 24-35 minutes were observed. Volumes of distributi on (V-d) were 3.2, 4.8, and 6.3 ml for PS2, MP, and PS, respectively, in comparison to 3.6 ml for sucrose, a fluid-phase marker. Relative ti ssue drug levels obtained at 1 and 24 hours after administration were kidney > liver > spleen > tumor > muscle, Total kidney and liver oligo nucleotide accumulation was approximately 7%-15% of the initial dose, with tumor accumulating 2%-3%, Intact compound was recovered from all tissues, including tumor, as assessed by high-pressure reversed-phase HPLC coupled to radiometric detection, Integrity of the oligonucleotid es ranged from 73% in blood to 43%-46% in kidney and liver, Kidney and liver appear to be the primary sites of metabolism, These results dem onstrate widespread tissue availability of these compounds and suggest their development as potential antitumor agents.