Microdialysis sampling in tumor and muscle: study of the disposition of 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (SR 4233).
Microdialysis sampling was used to study the pharmacokinetics and disposition of SR 4233 (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide), a representative of a new class of bioreductive antineoplastic agents. The pharmacokinetics of unbound SR 4233 in plasma was determined using a flexible microdialysis probe implanted into the jugular vein of conscious, freely-moving rats. No difference in the plasma pharmacokinetics was observed between healthy and tumor bearing rats. In both cases a biexponential decay following an i.v. dose was observed with t1/2 (alpha) of 13.4 +/- 3.2 minutes and t1/2 (beta) of 37.0 +/- 14.4 minutes. Binding of SR 4233 to plasma proteins was determined to be concentration independent at 21.4 +/- 2.9%. A linear microdialysis probe was used to sample solid tumor and muscle tissue in vivo to study the disposition of SR 4233 into these tissues. Similar elimination kinetics were observed in both tissues although the peak concentration of SR 4233 in muscle was 20 times that in the tumor. The extent of reductive metabolism was much greater in the tumor relative to muscle. This was observed after both a systemic dose of SR 4233 and direct dosing to the tissue through the microdialysis probe. This study demonstrates the potential of microdialysis sampling in vivo to the study of the disposition of drugs.
Palsmeier
R K
RK
Department of Chemistry, University of Kansas, Lawrence 66045.
Lunte
C E
CE
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D006207:Half-Life; D007601:Jugular Veins; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis / Q000295:instrumentation / Q000379:methods; D009132:Muscles / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D000077704:Tirapazamine; D014018:Tissue Distribution; D014227:Triazines / Q000097:blood / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine