Single doses of norfloxacin (200, 400, 800, 1,200, and 1,600 mg) or placebo were administered orally at weekly intervals to 14 healthy male volunteers in a double-blind study. Norfloxacin was measured in serum and urine by high-pressure liquid chromatography with UV detection. The concentrations of this drug in serum peaked 1 to 2 h after each dose; the mean peak values for increasing doses were 0.75, 1.58, 2.41, 3.15, and 3.87 micrograms/ml. Mean area under the serum concentration-time curves for the first 12 h after each dose were 3.56, 6.26, 11.4, 16.1, and 19.7 micrograms . h/ml, respectively. The elimination half-life of norfloxacin was about 7 h and was similar for all doses. The concentrations of the drug in urine also peaked 1 to 2 h after dosage; mean peak values for increasing doses were 200, 478, 697, 992, and 1,045 micrograms/ml. Renal clearances approximated 285 ml/min. About 30% of each dose was excreted into urine as unmetabolized norfloxacin. Crystals of the drug were occasionally observed during microscopic examination of freshly voided urine collected after the 1,200- and 1,600-mg doses. Crystalluria was not encountered at lower doses.
A high-performance liquid chromatographic method for the analysis of norfloxacin [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid], a new nalidixic acid analog, in human serum and urine is described. A statistical evaluation of the assay data showed acceptable accuracy and precision for 0.1 to 10.0 ,ug of MK-366 per ml of serum and for 1.0 to 500 ,ug of MK-366 per ml of urine. MK-366 was extracted from serum and urine at pH 7.5 with methylene chloride and back-extracted with sodium hydroxide solution. Chromatography was performed on an anion-exchange column with acetonitrilephosphate buffer as the mobile phase; UV absorbance was monitored at 273 nm. The method was used to measure MK-366 in clinical specimens.boxylic acid] is a new broad-spectrum antibacterial agent that is structurally related to nalidixic acid (Fig. 1). MK-366 exhibits greater antibacterial activity against both gram-positive and gram-negative bacteria than other nalidixic acid analogs and exhibits greater activity against Pseudomonas aeruginosa than gentamicin (1,2 Extraction of samples. Serum (1 ml) or urine (200 pul) was thoroughly mixed with 100 p.l of 0.05 N NaOH (containing standards preparing the standard curve) in a 40-ml glass extraction tube. Methylene chloride (11 ml) and 0.5 M sodium phosphate buffer (0.5 ml, pH 7.5) were then added, and the tubes were gently shaken for 10 min on a mechanical shaker. After phase separation by centrifugation at 1,500 x g for 5 min, 10 ml of the methylene chloride layer was transferred to a second 40-ml extraction tube. Fresh methylene chloride (11 ml) was added to the first extraction tube, and a second extraction was performed; 10 ml of the second extract was pooled with the first organic phase.
To investigate whether sulindac once daily in the evening might be equivalent to the currently recommended twice-daily dose schedule in sustaining plasma concentrations of bioactive sulfide metabolite, 12 healthy subjects received, in a randomized crossover study, sulindac, 200 mg b.i.d. (at 9:00 A.M. and 9:00 P.M.) and 400 mg once daily (at 9:00 P.M.), each for 7 days. At steady state the area under the plasma concentration-time curve (AUC) over 24 hr for sulfide metabolite was greater after once-daily dosing (112 and 84 micrograms . hr . ml-1, P less than 0.05), while mean trough concentrations did not differ. The greater AUC seemed to be related to diurnal variation in metabolite cumulation. A circadian rhythm was apparent at steady state during twice-daily dosing; the mean AUC and peak plasma concentration (C(max)) were greater between 9 A.M. and 9 P.M. than between 9 P.M. and 9 A.M. (50 and 34 micrograms . hr . ml-1; 6.85 and 4.23 micrograms/ml). Although C(max) values of sulfide were higher after morning doses of sulindac, it was apparent that much of the plasma sulfide after morning doses was actually derived from the previous evening dose. This may be a consequence of circadian rhythm in gallbladder emptying. While renal clearance of sulindac was related to urinary pH, diurnal changes in urinary acidity did not cause the fluctuations in the plasma sulfide. Since once-daily sulindac in the evening is as, if not more, effective than twice-daily drug in sustaining plasma sulfide levels, further studies on the therapeutic efficacy of once-daily dosing are warranted.
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