Pharmacokinetics of Aryldihydro-s-triazines with antifolate activity II: Blood levels and their relevance to antineoplastic activity in rats.
Blood levels of three aryldihydro-s-triazines in rats were followed: 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-phenyl-s-triazine (I), the prototype of the series; 4,6-diamino-1-(3,4-dichlorophenyl)-1,2-dihydro-2,2-dimethyl-s-triazine (II); and N-(m-tolyl)-p-(4,6-diamino-1,2-dihydro-2,2-dimethyl-s-triazin-1-yl)hydrocinnamide (III). The blood profiles obtained provide substantial evidence that III, but not II, was precipitated in the peritoneal cavity where it was injected. Precipitation after intraperitoneal injection may explain why III and similar triazines with long nonpolar chains have been reported to be more active against intraperitoneal Walker 256 tumor than is II, even though the latter compound is a far more potent inhibitor of Walker 256 dihydrofolate reductase and of tumor cell cultures in vitro. Precipitation in the peritoneal cavity also may be involved in the difficulty of obtaining the toxicity-free antineoplastic activity expected from certain aryldihydrotriazines selectively inhibiting neoplastic dihydrofolate reductase.
D000818:Animals; D000970:Antineoplastic Agents; D011232:Chemical Precipitation; D004121:Dimethyl Sulfoxide / Q000097:blood; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D013997:Time Factors; D014227:Triazines / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D014227:Triazines; D004121:Dimethyl Sulfoxide