Modulation of O6-alkylguanine-DNA alkyltransferase in rats following intravenous administration of O6-methylguanine.
The purine analogue O6-methylguanine is an effective biochemical modulator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase. Inactivation of the alkyltransferase by O6-methylguanine sensitizes tumor cells to nitrosoureas in vitro. The pharmacokinetics of O6-methylguanine were evaluated in female Sprague-Dawley rats following administration of a single 40 mg/kg i.v. bolus dose. Two-compartment pharmacokinetic analysis revealed a terminal elimination half-life of 2.3 +/- 0.68 h, a total body clearance of 6.0 +/- 0.53 ml/min/kg, and a volume of distribution at steady state of 948 +/- 186 ml/kg. To inactivate the alkyltransferase, 80 mg/kg O6-methylguanine was given at 0 and 2 h. Alkyltransferase decreased in bone marrow, kidney, lung, spleen, and intestine by 20-90%. Regeneration of alkyltransferase activity was observed 22-70 h after the first bolus dose of O6-methylguanine. A continuous infusion protocol, which achieved a steady state serum concentration of 10.3 +/- 1.5 micrograms O6-methylguanine/ml at 15 h, resulted in a similar degree of inactivation of tissue alkyltransferase to that observed following bolus drug infusion. O6-Methylguanine tissue concentrations, including that determined in brain, were 1.7- to 4-fold higher than that in serum, indicating that O6-methylguanine is concentrated in most if not all tissues. These studies establish pharmacokinetic parameters of O6-methylguanine in rats and suggest that effective biochemical modulation of alkyltransferase can be achieved in vivo. Further studies are indicated to assess the extent to which biochemical modulation of alkyltransferase reduces tumor nitrosourea resistance in vivo.
Dexter
E U
EU
Department of Medicine, University Hospitals of Cleveland, Ohio.
Yamashita
T S
TS
Donovan
C
C
Gerson
S L
SL
D000818:Animals; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D014018:Tissue Distribution
D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase