The pharmacokinetic properties of the anti-inflammatory agent, fenclozic acid, have been established in the dog, calf, sheep, and horse after intravenous administration and also in the rat, mouse, guinea pig, monkey, and man after oral dosage. At doses equivalent to those therapeutically effective in the rat, the pharmacokinetics of fenclozic acid are described in all species by the concept of the two-compartment open model. In all species, the compound is restricted mainly within the central compartment, the volume of which is less than 20% of the body weight. Due to serum protein binding, the vascular lymphatic system constitutes a large part of the central compartment volume. The biological half-life of fenclozic acid varies between 3 hr. in the monkey and 118 hr. in the horse; in the guinea pig, rat, dog, and man the half-life is in the range 26-31 hr. There is a direct relationship between the logarithm of the serum concentration and the activity in the adjuvant-induced arthritis test in rats. The pharmacokinetic information obtained has been used in the design of human clinical trials.
Keyphrases 0 Fenclozic and 14C-fenclozic acids-pharmacokinetic properties 0 Pharmacokinetic parameters-fenclozic acid in animals, humans 0 Arthritic subjects-fenclozic acid serum level relation, activity UV spectrophotometry-analysis 0 TLCseparation, identification
The experimental syndrome of adjuvant-induced arthritis in rats has been used in these laboratories for several years for the detection and evaluation of compounds that may have use in the treatment of rheumatoid arthritis in man (1). Fenclozic acid (I.C.I. 54,450) (Structure I) is one of a series of substituted phenylfenclozic acid [I.C.I. 54,450; 2-(p-chlorophenyl)thiazol-4-y1 acetic acid] Dosing Procedures-Fenclozic acid was administered orally to mice, rats, guinea pigs, and rhesus monkeys by stomach tube as a ball-milled suspension in an inert dispersing fluid. In dogs, fenclozic acid was administered intravenously as either the sodium or N- Scheme I-The two-compartment open model: k12, kzl, and k,] are fht-order rate constants; V, and VT are the volumes of the two compartments; and k, is a first-order absorption rate constant, when drug is administered by extravascular route.