Jens Aas Jansen

Indomethacin: Plasma concentrations and protein binding in man

SummaryThe fluorometric method of Holt & Hawkins (1965) has been modified to permit determination of 50 ng indomethacin in 0.5 ml plasma, by measuring its fluorescence in a phosphate buffer at pH 11.6 instead of sodium hydroxide. The method has also been adapted to show the presence of salicylic acid and a column chromatographic method has been devised for its removal. The protein binding of indomethacin in human plasma was calculated to be about 90% from an association constant of 0.86×103 M−1 (M=molarity). The number of binding sites on albumin is about 15. The plasma levels of indomethacin in patients receiving continuous treatment with Indocid® were between 0.5 and 3 µg/ml during the 4–5 h immediately after the last dose of 25 mg. The disappearance of indomethacin from plasma appears to consist of a fast primary phase at plasma concentrations greater than 1 µg/ml (T 1/2 about 90 min.), and a slower secondary phase.

Boric acid single dose pharmacokinetics after intravenous administration to man.

Eighth young adult male volunteers with a basic (alimentary) plasma boric acid concentration of <0.10–0.46 mg/l were given a single dose of boric acid (562–611 mg) by 20 min IV infusion. The plasma concentration curves, followed for 3 days, best fitted a three-compartment open model, although two subjects had to be left out due to inconstant basal plasma concentration values or failure to fit to the three-compartment model. The 120 h urinary excretion was 98.7±9.1% of dose, Cltot 54.6±8.0 ml/min/1.73 m2, t1/2β 21.0±4.9 h and distribution volumes V1, V2, and V3: 0.251±0.099, 0.456±0.067 and 0.340±0.128 l/kg.

Influence of indomethacin on the distribution of cortisol in man

SummarySimultaneous determinations of free and protein bound plasma cortisol and of the concentrations of cortisol in skin biopsies were performed after treatment with indomethacin. Neither after a single dose nor in patients on continuous treatment, were any consistent changes found in the protein binding of plasma cortisol. However, in patients treated for more than 3 weeks a significantly greater number of skin biopsies were observed with very low concentrations of cortisol. No relation between the free fraction of plasma cortisol and the tissue cortisol could be demonstrated.In vitro experiments showed no alteration of the protein binding of cortisol after the addition of indomethacin to plasma. It is concluded that indomethacin does not have antirheumatic activity because of displacement of the protein bound plasma cortisol as proposed by other workers. However, long term treatment with indomethacin does seem to influence the tissue distribution of cortisol. The possible relationship of this observation is discussed in view of reported fatalities after long continued indomethacin treatment.