Pirazolac (ZK-76604)

Pharmacokinetics of pirazolac--a new anti-inflammatory drug--in human volunteers. I. Absorption, disposition, biotransformation and excretion

The absorption, disposition, biotransformation and excretion of the nonsteroidal anti-inflammatory drug pirazolac were investigated in 6 volunteers (3 males, 3 females, age 50 greater than years) after intravenous and oral administration of 50 mg 14C-pirazolac as an aqueous solution of the sodium salt. Pirazolac was very rapidly and completely absorbed and bioavailable when orally administered in a dose of 50 mg in solution. Maximum pirazolac levels in plasma of 6 micrograms/ml (30% of dose in total plasma volume) were already reached after approx. 20 minutes. No metabolites were detectable in the plasma. Pirazolac was eliminated from the plasma in two phases with half-lives of 3 hours and 16 hours, respectively, regardless of administration route. After intravenous and oral administration approximately 80% of the dose was excreted with the urine and approximately 15% with the feces within 7 days, indicating a complete excretion of 14C-radioactivity. In urine, approximately 10% of the dose was identified as unchanged pirazolac and 70% as pirazolac ester glucuronide.

Pharmacokinetics of Pirazolac - a New Anti-Inflammatory Drug - in Human Volunteers II. Dose Linearity of Plasma Levels and Excretion

The concentration-time course of pirazolac in plasma and its urinary excretion were investigated in 6 young volunteers (3 males, 3 females) after oral administration of 50, 150, 300, 450, and 600 mg pirazolac as a crystalline suspension at weekly intervals. Only unchanged pirazolac was detected in the plasma. Maximum plasma levels and areas under the plasma level curve increased linearly with the dose. All other pharmacokinetic parameters such as tmax (3 h), oral clearance CL (0.3ml/min/kg) and terminal plasma half life t1/2 (16-18 h) were independent of the dose. A total of 65 % of the dose was renally excreted within 72 hours mainly as pirazolac glucuronide.

Differential dosing study of pirazolac, a new non-steroidal anti-inflammatory agent, in patients with rheumatoid arthritis

Twenty-four patients with classical or definite rheumatoid arthritis participated in a 4-week double-blind crossover study to compare the effectiveness of two different dosage regimens of pirazolac. Patients were allocated at random to receive 2-weeks' treatment with either 300 mg pirazolac in the morning and 600 mg at night or 450 mg pirazolac given morning and evening, and were then crossed over to the alternative regimen for a further 2 weeks. Physician assessments of disease activity were carried out on entry and at the end of each treatment period, and patients kept a daily record of visual analogue scale scores for pain and stiffness. The results showed that both dosage regimens of pirazolac produced a significant improvement in the parameters assessed, but the difference between the two regimens was not significant. However, overall assessment at the end of the trial by the 23 patients who completed the study showed that 14 preferred the 300/600 mg regimen compared with 7 who preferred the 450/450 mg regimen: 2 patients considered both regimens equally effective. Pirazolac was relatively well tolerated, only a few patients reporting gastro-intestinal (2) and skin (3) side-effects during the trial period.