1 Valproic acid or phenytoin were added to fresh human serum in varying concentrations and their binding characteristics determined by the method of Scatchard (1949). 2 Changes in serum albumin binding were investigated for phenytoin in the presence of 280, 560, 1050 and 2100 mumol l‐1 valproic acid, and for valproic acid in the presence of 40, 120, 280 and 480 mumol l‐1 phenytoin. 3 Phenytoin appeared to bind to a single site on the albumin molecule and could be competitively displaced from this site by concentrations of valproic acid above 280 mumol l‐1. 4 At high concentrations of valproic acid, the affinity of phenytoin for albumin was greatly decreased but the number of available binding sites was increased from one to four. 5 Valproic acid was bound to two high affinity and five low affinity binding sites but the latter were not detectable at valproic acid concentrations below 2100 mumol l‐ 1. 6 Phenytoin displaced valproic acid from its high affinity binding sites, although this was statistically significant only at a concentration of 480 mumol l‐1 phenytoin.
Healthy adult subjects were given oral sustained-release (SR) aminophylline tablets 225 mg 12-hourly (n = 12) or 450 mg 12-hourly (n = 6) for 5 doses, and all were given aminophylline 225 mg intravenously on a separate occasion to determine individual kinetic parameters. The mean plasma theophylline half-life ( 1 1/2) from the intravenous study was 5.8 hr (SD +/- 1.9). During the 12 hr after the fifth dose of SR aminophylline, the maximum and minimum mean (SD) plasma theophylline levels were 9.7 (3.2) mug/ml and 4.9 (2.0) mug/ml for the 225-mg dose, and 21.1 (2.2) mug/ml and 11.6 (4.4) mug/ml for the 450-mg dose. Side effects were generally mild in the low-dose study, but in the high-dose study 3 subjects reported headache and 1 was withdrawn after 3 doses. Two subjects also noted nausea, and 3 reported insomnia and anxiety in the high-dose study. It was concluded that there was a considerable range of doses needed to achieve adequate plasma levels, and that the formulation studied was capable of producing reasonably stable and satisfactory plasma theophylline levels once individual dose requirements had been established.
. The changes in antipyrine metabolism and urinary ratios of corticosteroid metabolites indicate hepatic enzyme induction which could account for the enhanced elimination of DL473 on repeated dosage.
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