Pharmacokinetics of oral O6-benzylguanine and evidence of interaction with oral ketoconazole in the rat.

Abstract

O6-Benzylguanine (BG) is a modulator of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT). BG is converted in mice, rats and humans to an equally active, yet longer-lived metabolite, O6-benzyl-8-oxoguanine (8-oxo-BG) by CYP1A2, CYP3A4 and aldehyde oxidase. Since intravenous BG is expected to enter phase I development with orally administered anticancer agents such as temozolomide, procarbazine or SarCNU, we determined the bioavailability of orally administered BG, as well as the effect of ketoconazole, a potent intestinal and hepatic CYP3A4 inhibitor, on the disposition of BG. Following intravenous or oral administration of BG in PEG-400/saline (40:60) to Sprague-Dawley rats, the pharmacokinetics of BG and 8-oxo-BG were determined. To determine the effect of CYP3A inhibition on disposition, oral BG was coadministered with ketoconazole. The peak plasma concentration (Cmax), time to Cmax (tmax), and bioavailability (F) of oral BG were: 2.3 +/- 0.9 microg/ml, 2.3 +/- 0.6 h, and 65.5% respectively. The AUCs of BG and 8-oxo-BG were 13.1 +/- 4.6 microg x h/ml and 1.7 +/- 0.4 microg x h/ml after oral administration of BG. Coadministration with ketoconazole resulted in an increase in mean absorption time from 2.0 +/- 0.3 h to 6.0 +/- 0.9 h, a shift in tmax to 5 +/- 3.3 h, a decrease in Cmax to 0.96 +/- 0.8 microg/ml, and a decrease in AUC0-inf ratio of 8-oxo-BG:BG from about 0.12 to 0.04 (P < 0.05). The bioavailability of BG was not changed (65.5% vs 56.9%, P= 0.78). The oral bioavailability of BG is high, warranting consideration of an oral formulation for clinical development. Coadministration of ketoconazole and BG resulted in delayed oral absorption and inhibition of conversion of BG to 8-oxo-BG in the rat model.