Abstract
Feprazone is a new member of the very large group of non-steroidal anti-inflammatory agents which are available for the treatment of inflammatory joint disease. It is a pyrazolidinedione derivative, related to phenylbutazone, but its disposition and metabolism had not been thoroughly investigated in man. A sequence of methods was followed in the present work, and initially radiolabelled feprazone was administered to subjects undergoing maintenance dosing with unlabelled drug. The results indicated that feprazone was efficiently absorbed and that the plasma elimination half-life of radioactivity was 29.5-33.5 h. Total excretion of radioactivity during the ensuing 7 days ranged from 46-87% of the administered dose with the faecal route accounting for 10% more than the renal route. Various gas and liquid chromatographic methods were developed to determine the concentration of feprazone and its hydroxy-metabolite in human plasma and urine. These procedures were capable of accurately measuring the compounds following both single and continuous drug dosage and were used to study pharmacokinetics in various clinical situations. Chromatography together with mass-spectrometry identified 4-(3'-hydroxy)feprazone as the only hydroxylated derivative of feprazone to be produced in man. Using the G.L.C. and H.P.L.C. methods, reference pharmacokinetic data was established in normal, healthy, young volunteers after administering both single and multiple doses of feprazone by different routes. The plasma elimination half-life of feprazone was considerably shorter than phenylbutazone, although the apparent volume of distribution and clearance were similar. Half-life was independent of the route of administration although compared with oral, rectal absorption was poor. Increasing the maintenance dose of feprazone resulted in a plateau occurring in the plasma level similar to that with phenylbutazone, but with a lower concentration. Pharmacokinetics of 4-(3'-hydroxy)feprazone were similar to those of gamma-hydroxyphenylbutazone.(1) Since metabolism and disposition of non-steroidal anti-inflammatory agents may be affected by disease states, pharmacokinetic studies with feprazone were undertaken in different patient groups in order to assess whether the drug could safely be administered to patients with a variety and combination of clinical problems. The elderly group exhibited mean pharmacokinetic parameters which were similar to normals, but the renally impaired patients exhibited decreased drug absorption although their mean plasma elimination half-life was similar to normal. The rheumatoid patients also absorbed feprazone less efficiently, but eliminated the drug in a similar manner to normals. In conclusion, there were few significant differences between normal volunteers and patients in their handling of feprazone, except that bioavailability was decreased in some patients. The present studies indicate that feprazone would be a safer drug to use in clinical practice than phenylbutazone. (1) During the course of phenylbutazone metabolism studies the prefix -gamma has been used extensively by previous workers to denote the (o-1) position and this precedent has been continued throughout this thesis.