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

Abstract

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 III. Steady state plasma levels

“…The time to reach steady state is in complete agreement with a value of 3.6 days (=5 half-lives) expected for theoretical reasons. Terminal half-life of 17.5 ± 4 h after cessation of treatment in the present study were equal to half-lives determined in young healthy volunteers after single administration (17.5 ± 2.7 hours) and equal to those in elderly subjects (tIn = 16.7 ±3 hours) (3,4). Dose linearity of steady state levels and equal halflives after multiple dosing compared to values from single dose experiments confirm that pirazolac exhibits first order pharmacokinetics over its whole therapeutic dose range.…”

“…[3] Steady state trough concentrations in the plasma Figure 1 shows the building-up of the PAA steady state levels (trough values) during both dosage regimens investigated. After b.i.d.…”

“…Approximately 85 % of the dose administered is excreted with the urine mainlyas PAA-ester-glucuronide. 15 % are excreted with the faeces (3). The pharmacokinetic behaviour of PAA after single administration proved to be dose linear over the whole therapeutic dose range (4).…”

“…Furthennore the plasma level of PAA after the last administration wasmonitored and disposition half-lives calculated were compared to those found after single administration (3,4). …”