Pharmacokinetics of the antirheumatic proquazone in healthy humans

The pharmacokinetics of the antirheumatic proquazone and its conjugated and unconjugated m-hydroxy metabolites were investigated in five healthy male volunteers after both intravenous (75 and 122 mg) and peroral (300 and 900 mg via capsules) administration. For adequate intravenous dosing of the poorly water-soluble proquazone, advantage was taken of the high degree of protein binding of the drug. Proquazone was admixed with 40% sterile human albumin, and these proteinaceous drug-containing solutions were injected. The pharmacokinetics of proquazone and of the measured metabolites after intravenous administration and after the 300-mg po dose were first order, whereas deviations from linear kinetics were observed at the 900-mg dose level. The apparent half-lives of the alpha, beta, and gamma phases of proquazone in plasma were 2, 14, and 76 min, respectively, on intravenous administration. The total clearance of proquazone was 700 mL/min, which indicated a high hepatic extraction. The apparent volume of distribution at steady state was 40 L, implying extensive binding or partitioning of the lipophilic drug in the tissues. Unchanged proquazone (less than 0.001%), the m-hydroxy metabolite (less than 1.0%), and the conjugated m-hydroxy metabolite (20%) were renally excreted after intravenous administration. The extent of absorption of proquazone was approximately 7% and was entirely the result of a large first-pass effect. Digital computer analysis of the data after intravenous administration was performed with a linear three-compartment model. A model-independent approach was used in the analysis of the peroral data.