Aminoglutethimide bioavailability, pharmacokinetics, and binding to blood constituents.

The bioavailability of aminoglutethimide tablets was examined using a spectrophotometric assay. For six subjects receiving 500 mg of aminoglutethimide as an oral solution, the average peak concentration was 6.2 micrograms/ml with a median time of 0.8 hr. The corresponding average peak concentration for tablet administration was 5.9 micrograms/ml with a median time of 1.5 hr. Average values for the area under the curve (AUC) extrapolated to infinity were 89.0 and 96.8 micrograms hr/ml for the solution and tablets, respectively. The tablets had a 9% larger mean for the AUC than the solution and a 5% lower value for the mean maximum concentration. The bioavailability of the tablets is considered equal to that of oral solution. Data for individual concentration versus time curves were treated by nonlinear least-squares curve fitting. A two-compartment model with first-order absorption gave an acceptable fit for most data sets, but the individual absorption rate coefficients were not reliably determined. Values were estimated for plasma clearance, renal clearance, and volume of distribution. The distribution of aminoglutethimide between plasma and cells of human blood was examined in vitro; the drug concentration in cells was 1.4-1.7 times the concentration in plasma. The binding of aminoglutethimide to plasma proteins of human blood was measured by equilibrium dialysis at starting concentrations of 5 and 10 micrograms/ml. The binding ranged from 21.3 to 25.0% without concentration dependence.

Biological disposition of sodium dichloroacetate in animals and humans after intravenous administration.

Sodium dichloroacetate, a potential antidote for lactic acidosis, was administered intravenously to rats, dogs, and four humans. In three rats, maximum plasma sodium dichloroacetate concentrations were 120-164 microgram/ml after a 100-mg/kg dose and declined with half-lives of 2.1-4.4 hr. In two dogs, maximal concentrations of 447 and 508 microgram/ml were attained after a 100-mg/kg dose. The subsequent decline was relatively slow with approximate half-lives of 17.1 and 24.6 hr. An intravenous infusion of 10 mg/kg was administered over 20 min to two human subjects. Two other subjects received 20 mg/kg. After the infusion, maximum plasma concentrations of 19.9 and 24.7 microgram/ml were seen with the lower dose and 57.3 and 74.9 microgram/ml were achieved with the higher dose. Thereafter, concentrations declined rapidly with half-lives of 20-36 min. The observed large interspecies differences in half-lives could be explained in terms of differences in the apparent volume of distribution and/or clearance.