Pharmacokinetic study of 4'-acetamidophenyl-2-(5'-p-toluyl-1'-methylpyrrole)acetate in the rat.
A pharmacokinetic study has been performed on a new non-steroidal anti-inflammatory drug, AU-8001 (4'-acetamidophenyl-2-(5'-p-toluyl-1'-methylpyrrole)acetate, CAS 82239-77-8) in the rat, following intravenous (10 mg/kg) and oral (50 mg/kg) administrations. The new molecule constitutes a prodrug of paracetamol and tolmetin. Compartmental and non-compartmental treatment of experimental data lead to the same conclusions. After intravenous administration, the rapid hydrolysis of the ester function of the molecule causes a short transit of the prodrug in the organism and the rapid attainment of maximum plasmatic levels of metabolites. After oral administration, the prodrug shows flip-flop behaviour in which the absorption constant rate is the limiting factor and is responsible for the slow bioconversion of the substance. The bioavailability of the prodrug is incomplete and, according to the urinary excretion data, a fraction of the dose reaches the blood stream in the form of metabolites. AU-8001, however, in spite of its limited bioavailability, is a model prodrug which could be used to prolong the activity of the original drugs.
Sabater
J
J
Research Department of Aldo-Union Laboratories, Esplugues, Barcelona, Spain.
Domenéch
J
J
Obach
R
R
D000082:Acetaminophen / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001682:Biological Availability; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D011355:Prodrugs; D051381:Rats; D017208:Rats, Wistar; D013535:Suspensions; D014018:Tissue Distribution; D014046:Tolmetin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D013535:Suspensions; D000082:Acetaminophen; C035894:AU 8001; D014046:Tolmetin