Effects of plasma protein binding displacement on the pharmacokinetics, tissue and tumor concentrations and efficacy of brequinar, a highly protein-bound antitumor agent.
Brequinar is a developmental antitumor agent which is highly bound to plasma proteins. The effects of plasma protein binding displacement on brequinar pharmacokinetics, tissue distribution, tumor distribution and antitumor efficacy were evaluated. Sodium salicylate and ibuprofen increased the percentage of free brequinar in serum in vitro, in proportion to their added concentrations. Sodium salicylate also altered the pharmacokinetics of i.v. brequinar in rats when adminstered i.v. or p.o. at 10- or 50-fold higher doses than brequinar. At the highest salicylate/brequinar dose ratio, significant increases were observed for terminal half-life, mean residence times in the body and tissues, systemic clearance, distribution clearance, the volume of the central compartment and volume of distribution at steady state. Neither salicylate nor ibuprofen increased brequinar concentrations in lung and muscle specimens from rats, 4 or 24 hr after dosing. Tumor, lung and muscle brequinar concentrations in mice were also unaffected by coadministered sodium salicylate, 4 or 24 hr after a single i.v. brequinar dose. In rats infused for 48 hr with brequinar or brequinar plus salicylate, salicylate increased the percentage of free brequinar in plasma and lungs, but total brequinar concentrations were reduced. Antitumor efficacy was evaluated by measuring the survival times of mice implanted with L1210 leukemia cells. Salicylate-treated mice had a similar brequinar dose/response profile as mice not coadministered salicylate. Ibuprofen also did not increase brequinar's antitumor potency.
Aungst
B J
BJ
Du Pont Medical Products, Wilmington, Delaware.
Blake
J A
JA
Rogers
N J
NJ
Dusak
B A
BA
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D011485:Protein Binding; D051381:Rats; D011917:Rats, Inbred Lew; D014018:Tissue Distribution; D011798:Quinaldines
D000970:Antineoplastic Agents; D001241:Aspirin; D001713:Biphenyl Compounds; D001798:Blood Proteins; D007052:Ibuprofen; C046943:brequinar; D011798:Quinaldines