Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis-Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady-state phenytoin serum concentrations resulting from different daily doses: The observed steady-state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p less than 0.02). The average deviation between observed and predicted levels was 0.04 mug/ml (range, +/- 3.2 mug/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r= 0.360, p less than 0.05). The average deviation was --3 mug/ml (range, 3.9 to --11.3 mug/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.

A system developed to expose chronically a large number of small animals to 918-MHz microwave has been modified to permit exposure at 2450 MHz. Special transmitting and termination transducers were used to retrofit the exposure chambers of the 918-MHz system. The use of separate cells that consist of cylindrical waveguides, which are excited by circularly polarized, guided waves, provides a relatively constant and easily quantifiable coupling of microwave energy to each animal, regardless of their position, posture, or movement. The VSWR in each cell is sufficiently low that any number of cells can be coupled to a single source through a power splitter without the need for an isolator.

No abstract

A megabore column gas-liquid chromatographic method which uses nitrogen-phosphorus detection was developed for the analysis of fluconazole in plasma, serum, cerebrospinal fluid, or urine. The assay was linear from 0.2 to 200 ,Ig/ml and had an average coefficient of variation of 7%. The suitability of the assay for pharmacokinetic studies was demonstrated.Fluconazole 858; 2-(2,4-difluorophenyl)-1,3-bis (lH-1,2,4-triazol-1-yl)-2-propanol; Fig. 1] is a triazole compound with potent antifungal activity which is currently being evaluated in clinical trials (5). It is well absorbed after oral administration (4) and shows good penetration into cerebrospinal fluid (1, 3). Early analytical methods for assay of this compound in biological fluids, designed to support preliminary animal and human studies, were effective but rather complex. Both gas-liquid chromatographic and highperformance liquid chromatographic (HPLC) approaches were used (2, 3, 6). However, with this compound now in clinical trials, a simpler and more rapid and reliable analytical method was desirable for therapeutic drug monitoring. We therefore developed the following method, which uses megabore column gas-liquid chromatography with nitrogenselective detection. MATERIALS AND METHODSInstrumentation. A Varian 6000 (Varian Instruments, Walnut Creek, Calif.) gas chromatograph with a nitrogen-phosphorus detector operating at an applied voltage of 5 to 10 mV was employed. A fused silica DB-5 megabore column (45 m long, inner diameter of 0.55 mm; J. W. Scientific, Folsom, Calif.) with a 1-,um-thick bonded liquid phase was used. The instrument conditions were as follows: injector temperature, 225°C; detector temperature, 275°C; column temperature, 1900C.Reagents. Fluconazole and internal standard UK-54,373 Standards and controls. Plasma standards were prepared by adding appropriate amounts of fluconazole in methanol to tubes that had been washed in a chromic acid bath and then sonicated in water purified by ion exchange, carbon filter, and 0.45-,um filter. The methanol was removed either by blowing nitrogen or air into the tubes at room temperature or by vacuum. ,ug/ml were employed in each group of urine specimens analyzed. Controls of 2 and 7 ,ug of fluconazole per ml, prepared in the same manner as were the standards, were also included in each group of serum or urine specimens assayed.Assay procedure. To assay plasma, serum, or cerebrospinal fluid, 0.5 ml of specimen was pipetted into a tube fitted with a Teflon-lined cap. One level spoonful of a Coors 01 spatula filled with NaHCO3-Na2CO3 (2:1) was added to the specimen to adjust the pH to 9.0 and to provide a salting-out effect. A 10-ml sample of extracting solvent (methylene chloride containing 0.1875 ,g of the UK-54,373 internal standard per ml) was added to the tube, and the mixture was mechanically shaken for 15 min. The tube was subsequently centrifuged in a floor model centrifuge (model CU-5000; International Equipment Co., Needham Heights, Mass.) for 5 min at 2,000 rpm. The upper aqueous layer was ...