David G. Kaiser

The effect of the dosage form on serum levels of indoxole

The influence of dosage form on serum levels of indoxole (2,3‐bis‐[p‐methoxyphenyll]‐indole), an anti‐inflammatory agent with low water solubility, was studied. Serum concentrations (fluorometric assay) were observed for 16 hours after the last dose in a short‐term multiple‐dose tolerance study when the compound was administered orally at four dose levels in Lipomul‐Oral emulsion. A good dose response was obtained when the average serum concentrations of individual subjects in the last dosage interval were plotted against the milligram per kilogram dose. Serum concentrations were also measured after oral administration at two dose levels in four different dosage forms. The order of serum level response was: Lipomul‐Oral emulsion ≃ soft elastic capsule 〉 aqueous suspension 〉 powder in a capsule. Potency estimates were 1.00: 1.10: 0.47: 0.16 following the first dose and 1.00: 0.72: 0.27: 0.16 following the sixth dose for the emulsion, soft elastic capsule, aqueous suspension, and powder in a capsule, respectively. Additional information is reported and discussed. The advantage of defining the serum level of a drug after the first dose and during a dosage interval at the equilibrium state is pointed out. The attempt to measure peaks and nadirs of drug concentration in the blood in multiple dose studies is less desirable than the method described above.

Pharmacokinetics of flurbiprofen

Both radiolabeled and nonlabeled drug have been used to study the pharmacokinetics of flurbiprofen (Ansaid, Upjohn). Drug absorption is rapid, drug disappearance half-life is independent of oral dose, and the area under the plasma drug concentration versus time curve increases with increasing oral dose. Elimination of intact drug from the peripheral circulation is biphasic and rapid. Following a single oral dose of 100 mg of flurbiprofen, drug bioavailability is equivalent using regimens of four 25-mg tablets, two 50-mg tablets, or one 100-mg tablet once daily. Long-term administration of flurbiprofen appears neither to inhibit nor induce the drugs metabolism.

Pharmacokinetics of 4,5‐bis(p‐methoxyphenyl)‐2‐phenylpyrrole‐3‐acetonitrile in normal and polyarthritic rats

4,5-Bis(p-methoxyphenyl)-2-phenylpyrrole-3-aceton~trile (U-24,568, I) is a potent, orally-active anti-inflammatory agent in the adjuvant-induced polyarthritic rat (Kaiser & Glenn, 1972) and is more active than aspirin or ibuprofen in the treatment of rheumatoid arthritis, but also more toxic (Brooks, Schmid & others, 1970). Kaiser & Glenn (1972) developed a fluorometric method for the determination of I in biological materials and reported that: (a) plasma concentrations in the polyarthritic rat were linearly related to oral dose; (b) anti-inflammatory activity was linearly related to the logarithm of the average plasma concentration in a dosage interval at the equilibrium state; and (c) disappearance of I from circulation in normal rats was slow (half-life, -1 1.4 h).

Gas chromatographic determination of guanadrel in plasma and urine

To evaluate the pharmacokinetics and drug availability from various dosage formulations, a method for the determination of guanadrel, (1,4-dioxaspiro[4,5]dec-2-ylmethyl)guanidine, in plasma and urine was required. A gas chromatographic procedure, based on formation of a hexafluoroacetylacetone derivative in a two-phase system of water and toluene, was developed. The limit of determination of the method is 5 ng/ml guanadrel in plasma and 15 ng/ml guanadrel in urine. Statistical analyses indicate average recoveries of 98.1 +/- 18.0 and 104.4 +/- 15.6% from plasma and urine, respectively. Mass spectrometric analyses, in conjunction with gas chromatography, confirmed the specificity of the method for intact drug. The procedure was applied successfully to drug absorption studies in humans.