A mixed-phase liquid chromatographic column was used to assay fluconazole in plasma, serum, and cerebrospinal fluid. The assay was linear from 0.2 to 20 tLg/ml, with an average coefficient of variation of less than 5%. The partitioning of the drug between serum and cerebrospinal fluid was determined for 34 patients.The method was demonstrated to be suitable for both pharmacokinetic studies and monitoring of patients receiving treatment with this antifungal agent.Fluconazole is part of a growing family of triazole antifungal drugs which exhibit a broad spectrum of activity. It has desirable pharmacologic properties, including a relatively long half-life, the ability to be administered either orally or parenterally, and good penetration into cerebrospinal fluid (CSF) (1,3,5). With respect to side effects, it is superior to imidazole antifungal drugs introduced earlier (8). It has already been approved by the U.S. Food and Drug Administration for the treatment of certain systemic fungal infections and is currently in clinical use in the United States and Europe as well as in clinical trials for other applications. A continuing increase in systemic fungal infections concomitant with growing immunosuppressed population established the relevance of fluconazole in the drug treatment arena. ' Several assays are currently in use for determining fluconazole concentrations in biologic specimens. Both gas-liquid chromatographic (2, 4) and high-performance liquid chromatographic (HPLC) (7) assays have been reported. Bioassay techniques are also available (6).The assay described in this report is an HPLC method that is done with a m-ixed-phase column and UV spectrophotometric detection. It has been developed for determining drug concentrations in serum, plasma, and cerebrospinal fluid (CSF).MATERIALS AND METHODS Instrumentation. A model 5020 (Varian Instruments, Walnut Creek, Calif.) liquid chromatograph with a variablewavelength UV detector (Varian UV-50 or equivalent) was used. A Varian mixed-phase PTHAA-5 liquid chromatographic column (15 cm long; 4-mm inner diameter) was used.Reagents. Fluconazole and internal standard UK-54,373 [2 -(2,4 -difluorophenyl) -1,3 -bis(lH -1,2,4 -triazol -1 -yl) -2-propanol; Fig. 1 Chromatographic conditions. The mobile phase was prepared by mixing acetonitrile with filtered 0.051 M monobasic phosphate buffer adjusted to pH of 3.0 at 15:85 (vol/vol). The flow rate was 0.9 ml/min. The UV detector was set at a wavelength of 210 nm. The HPLC apparatus was operated at room temperature (25 to 28°C).Standards and controls. Stock standards at concentrations of 1 and 100 ,ug/ml in methanol were prepared by placing appropriate amounts of fluconazole in polypropylene tubes with screw-cap tops and then adding 0.10 ml of methanol. Working serum standards with fluconazole concentrations of 0.0, 0.2, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 40.0, 50.0, and 100 ,ug/ml were prepared by placing various amounts of the two stock standard solutions in 15-ml glass tubes, taking the methanol to near dryness, an...
The purpose of this study was to investigate the effect of norfloxacin on theophyiline elimination. Ten normal volunteers were studied. In a randomized crossover sequence, each subject received 6 mg of aminophyiline per kg of body weight by a 30-min intravenous infusion on day 4 of taking norfloxacin (400 mg every 12 h) or while drug free. Mean theophylline clearance decreased and mean elimination half-life increased after norfloxacin administration (from 0.036 ± 0.006 to 0.033 + 0.004 liter/h per kg and from 8.7 + 1.2 to 9.5 + 1.5 h, respectively; P < 0.05, Wilcoxon signed-ranks test). We conclude that norfloxacin taken in recommended doses for 3 days has a small inhibitory effect on theophylline metabolism that would probably not cause clinically important elevations in theophylline concentrations in most patients.Norfloxacin is a new quinolone antimicrobial agent recently approved for clinical use by the Food and Drug Administration. Coadministration of theophylline with three structurally related compounds, enoxacin, pefloxacin, and ciprofloxacin, has been reported to increase theophylline concentrations and cause toxicity (2,8,11,(13)(14)(15)(16); coadministration with nalidixic acid, another quinolone, does not (16). Ofloxacin has been reported to decrease or have no effect on theophylline clearance (3,5,16). It has been postulated that the 4-oxoquinolone metabolites rather than the parent drug cause the drug interaction (6, 16). Norfloxacin is metabolized to such a compound (17). We therefore sought to determine the effect of norfloxacin on theophylline pharmacokinetics.The purposes of this study were to (i) investigate the effect of norfloxacin on theophylline clearance and (ii) determine if any specific metabolic pathway is affected.MATERIALS AND METHODS Study population. Ten healthy, nonsmoking adults (four females and six males, ages 22 to 38) participated in the study, which was approved by the Human Research Review Committee at our institution. All subjects had normal results for physical examinations, urinalysis, and hematologic and biochemical studies. All subjects were within 10% of their ideal body weight (range, 54 to 89 kg).Drug administration. In a randomized, crossover sequence, subjects were administered 6 mg of aminophylline per kg of body weight by intravenous infusion over 30 min on day 4 of taking norfloxacin (400 mg every 12 h) or while drug free. The study periods were separated by 1 week. Subjects abstained from alcohol, foods known to induce drug metabolism, and other drugs for at least 72 h prior to receiving any study drug. Subjects also abstained from caffeine for at least 48 h prior to receiving aminophylline.Sample collection. Blood was taken from an indwelling cannula immediately before and 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after the aminophylline infusion. The blood was allowed to clot at room temperature, the samples were centrifuged at 800 x g, and the serum was collected. Urine was collected 0 to 24 h after aminophylline administration. * Correspondin...
We compared 56 paired measurements of osmolal gaps and serum ethyl alcohol levels in 15 anesthetized dogs. We then repeated these comparisons after correcting the osmolal gaps for the preceding (the administration of ethyl alcohol) difference between measured and calculated osmolalities. No statistical differences were observed between ethyl alcohol levels and either uncorrected or corrected osmolal gaps. However, uncorrected osmolal gaps differed from ethyl alcohol levels by less than 5 mmol/L in 39.3% of the measurements and by more than 10 mmol/L in 19.6% of the measurements. Corresponding percentages for corrected osmolal gaps were 94.6 and 0 respectively. Thus uncorrected osmolal gaps offer a rough screening test, whereas corrected osmolal gaps offer accurate predictions of serum ethyl alcohol levels.
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