Bioavailability of oral dexamethasone.

Bioavailabilities of dexamethasone tablets and elixir in man were evaluated by each of 3 model-independent methods of pharmacokinetic analysis employing plasma and urinary values as determined by radioimmune assay. There were no significant differences among the results determined by the 3 methods nor between the respective availabilities of the two formulations; the latter averaged 82.6 +/- 17.7% for the elixir formulation and 78.0 +/- 12.1% for tablets.

The disposition of sulindac.

The disposition of sulindac, a new nonsteroid anti-inflammatory drug, has been studied in normal volunteers in five separate clinical studies. Based upon material balance considerations, a minimum of approximately 88% of an oral dose is absorbed. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide. The latter, which all available evidence indicates to be the pharmacologically active form of sulindac, is not excreted in urine, and has an apparent terminal half-life of 18.2 hr, well suited to twice daily dosage of its pro-drug. Following twice daily dosage of sulindac for 5 days, plasma levels of sulfide approach an apparent steady state with concentrations varying only within a twofold range over each dosage interval. The reversible biotransformation between sulindac and its active sulfide metabolite provides the basis for two therapeutic advantages relating to the gastrointestinal intolerance usually associated with anti-inflammatory drugs: (1) circumvention of initial exposure of gastric and small intestinal mucosa to the active form of the drug and (2) maintenance of systemic levels of active drug by means of enterohepatic recycling, principally of inactive pro-drug.

Bioavailability of dexamethasone. II. Dexamethasone phosphate.

Plasma levels of dexamethasone phosphate (DP) and dexamethasone free alcohol (DA) were determined by a modification of existing radioimmunoassay methodology following intravenous administration of DP in man. Areas under DA plasma profiles were a linear function of DP dosage over the 40-fold range 0.05 to 2.0 mg/kg, and, by comparison with values obtained after DA was intravenously administered, indicated an overall conversion of DP to DA of 90%. The first-order rate constant for the conversion, 4.03 hr-1, was approximately 25 times that for hydrolysis in whole blood incubated in vitro. This relationship as well as disposition kinetics suggested that the major component of DP hydrolysis occurs within highly perfused organ(s) comprising the central kinetic compartment. Eighteen subjects were studied in a crossover experiment, and no significant differences were observed in best-fit parameters for the 4 mg/ml parenteral solution of DP in current use and an experimental high potency preparation of 24 mg/ml.

Radioimmunoassay of indomethacin in biological fluids.

A radioimmunoassay was developed for the determination of indomethacin in biological fluids at concentrations as low as 50 ng/ml. Antibodies were produced in rabbits immunized with a conjugate of bovine serum albumin and indomethacin. This conjugate was prepared by an N-hydroxysuccinimide active ester procedure. Antiserums exhibited minimal cross-reactivity with the O-desmethyl and deschlorobenzoyl metabolites. However, the glucuronide conjugate was about three times as reactive as indomethacin, thus invalidating direct determinations of indomethacin in urine. This difficulty was circumvented by analyzing urine aliquots before and after conjugate hydrolysis. Concentrations of free and conjugated indomethacin were calculated by difference.

Analysis of sulindac and metabolites by combined isotope dilution-radioimmunoassay.

Sulindac, a new anti-inflammatory agent, and its sulfone and sulfide metabolites were conjugated to bovine serum albumin by the N-hydroxysuccinimide active ester procedure. Antiserum from rabbits immunized with each of these haptens exhibited extensive cross-reactivity, precluding differential analyses of the three species by displacement assay without prior separation. Therefore, an analytical method based on a combination of isotope dilution and radioimmunoassay was devised. A known mixture of the three chemical species, each labeled with tritium, was equilibrated with plasma or urine samples, reisolated chromatographically, and quantitated by binding to an appropriate immunoglobulin. The radiolabeled materials thus served as recovery standards as well as labeled antigens for each displacement assay. Sulindac and each of its metabolites in plasma or urine at concentrations as low as 500 ng/sample were differentially determined by this procedure. However, since an extraction is required, several milliliters of plasma can be used for each sample, thus increasing the actual sensitivity of the assay.