Thiolytic cleavage and binding of the antitumour agent CI-921 in blood.
The antitumour agent 9-[[2-methoxy-4-[methylsulphonylamino]-phenyl]amino]-N,5-dimethyl- 4-acridinecarboxamide (CI-921; NSC 343499) is currently undergoing clinical evaluation. The plasma disposition of this compound together with its ability to bind to plasma proteins has been investigated in the mouse. Five minutes after intravenous administration of [acridinyl-G-3H]-CI-921 (57.7 mol/kg) to male BDF1 mice, plasma samples were taken and precipitated with acetonitrile. 17% of the total plasma radioactivity was found to be bound to plasma proteins, increasing to 31% by 30 min. To ascertain the mechanism of binding, [acridinyl-G-3H]-CI-921 was incubated at 37 degrees C in mouse blood or plasma and the radioactivity analysed after precipitation with acetonitrile. CI-921 and the cleavage product 4-amino-3-methoxy-methanesulphonanilide (MSA) were detected in the acetonitrile supernatants by HPLC using electrochemical and ultraviolet detection. After incubation for 1 h with blood, extensive association of radioactivity (80% of total) with plasma proteins, together with a rapid decrease in CI-921 concentration and a concomitant increase in MSA concentration, was observed. In blood samples from mice given CI-921, low concentrations (1 to 2 mumol/l) of MSA were detected up to 1 h after injection. The results suggest that in vivo at least part of the covalent binding in blood arises from the nucleophilic attack by protein thiols at the C-9 position of the acridine ring resulting in covalent protein adducts and release of MSA.
Kestell
P
P
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Paxton
J W
JW
Robertson
I G
IG
Evans
P C
PC
Dormer
R A
RA
Baguley
B C
BC
D000097:Acetonitriles / Q000378:metabolism; D000677:Amsacrine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013455:Sulfur / Q000378:metabolism*
D000097:Acetonitriles; D000970:Antineoplastic Agents; D001798:Blood Proteins; D000677:Amsacrine; D013455:Sulfur; C042315:asulacrine