O6-Benzyl-2′-deoxyguanosine is a potential antitumor drug modulator that is intended to reduce or eliminate O6-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 O6-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 O6-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 O6-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 O6-benzyl-2′-deoxyguanosine and O6-benzylguanine at concentrations which are considered to be effective in depleting alkyltransferase activity. Levels of the nucleoside reached a maximum of 45 μM at 2 h, while those of O6-benzylguanine peaked to 20 μM at 4 h and remained at that level for at least 4 more hours. Transport of O6-benzyl-2′-deoxyguanosine in C6 glioma cells increased linearly with the extracellular concentration of the drug up to 600 μM. Intracellular levels of the drug reached 1.2 pmol per μM of extracellular compound per 106 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 O6-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 β-glucuronidases could restore the inhibitory effect of the drug in the colon, which could have pharmacologic implications in the treatment of colon cancers.
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