Metabolism and disposition of O super(6)-benzyl-2'-deoxyguanosine in Sprague-Dawley rats

O super(6)-Benzyl-2'-deoxyguanosine is a potential antitumor drug modulator that is intended to reduce or eliminate O super(6)-alkylguanine-DNA alkyltransferase activity in tumors prior to treatment with genotoxic chemotherapeutic alkylating agents. The rationale for using this compound instead of the more active O super(6)-benzylguanine and its substituted benzyl derivatives at the benzyl ring is its greater solubility in aqueous media and potential pharmacologic advantage. Metabolism and disposition of O super(6)-benzyl-2'-deoxyguanosine was determined in adult male Sprague-Dawley rats following an ip injection of 100 mg/kg. Under these conditions, the compound was partially metabolized to yield a glucuronic acid conjugate, which was secreted exclusively in the bile. Removal of the 2'-deoxyribose or the benzyl group to yield O super(6)-benzylguanine and 2'-deoxyguanosine, respectively, occurred to a lesser extent. Metabolism accounted for the clearance of at least 58% of the total dose and took place primarily in the liver. Direct excretion of unchanged drug, mainly in urine, accounted for the remainder of the dose. Analysis of venous blood showed the presence of O super(6)-benzyl-2'-deoxyguanosine and O super(6)-benzylguanine at concentrations which are considered to be effective in depleting alkyl-transferase activity. Levels of the nucleoside reached a maximum of 45 mu M at 2 h, while those of O super(6)-benzylguanine peaked to 20 mu M at 4 h and remained at that level for at least 4 more hours. Transport of O super(6)-benzyl-2'-deoxyguanosine in C6 glioma cells increased linearly with the extracellular concentration of the drug up to 600 mu M. Intracellular levels of the drug reached 1.2 pmol per mu M of extracellular compound per 10 super(6) cells as soon as 30 s after exposure and remained as high for at least 1 h. Such levels indicate that entrapment of the nucleoside inside cells by either phosphorylation or other means is probably not an important feature for this drug. The extensive glucuronidation of O super(6)-benzyl-2'-deoxyguanosine may result in the inactivation of the drug as an alkyltransferase inhibitor, thus protecting the intestinal epithelium from being sensitized to alkylating agents. However, hydrolysis of the conjugate by bacterial beta -glucuronidases could restore the inhibitory effect of the drug in the colon, which could have pharmacologic implications in the treatment of colon cancers.