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Acute effects of amiloride (5 mg) (A), hydrochlorthiazide (50 mg) (H) and the combination (50 + 5 mg) (HA) on urinary electrolyte excretion and pH of ten healthy volunteers – taking placebo five times and twice randomly A and HA and once H – were studied during one day.Amiloride showed a natriuretic effect, which in combination was additive to that of hydrochlorthiazide, but the excretion of water did not increase significantly after A. The urinary excretion of potassium decreased with amiloride below normal levels and was at the level of placebo after the combination (HA). There was a striking linear correlation between urinary sodium and potassium with all the drugs, although showing with A a higher potassium retention during high sodium excretion. Urinary pH rose after A and HA during the first 8 hours, but this effect was not seen, however, after H.No significant differences in the effect of the two brands of A (Medamor® and Puritrid®) on the urinary electrolyte excretion and pH, nor in those of the two brands of HA (Moduretic® and Amitrid®) were found. Similarly, the plasma concentrations of hydrochlorthiazide, determined gas chromatographically, were equal after Moduretic® and Amitrid® tablets. The systemic availability of H was faster in the combination of HA than alone. In the AUC value of H, however, there was no significant difference between HA and H tablets.

The pharmacokinetic profile of pipemidic acid was studied in two groups of young healthy volunteers by using a new, sensitive, high-pressure liquid chromatography procedure for quantitation of pipemidic acid in biological fluids. After oral or intravenous administration, the disposition of pipemidic acid may be described as a one- or a two-compartment open model, respectively. Oral bioavailability was 93.1 +/- 11% (mean +/- standard error). After administration of a 100-mg tablet, 13.4 +/- 2.7% was bound to serum proteins at the time of peak drug concentration in serum. Excretion of pipemidic acid in saliva was negligible, the saliva/serum ratio being about 0.32. At steady state after the twice-daily administration of a 500-mg tablet, which is a recommended dosage regimen, a peak drug concentration in serum of 4.3 +/- 0.5 micrograms/ml was attained in 1.2 +/- 0.1 h. The apparent volume of distribution was 1.9 +/- 0.2 liters/kg, and the elimination half-life was 3.4 +/- 0.2 h. The renal clearance was 4.3 +/- 0.7 ml/min per kg, and the total clearance was 6.3 +/- 0.5 ml/min per kg. Despite a considerable water load, the minimum concentration in urine at the end of a dosing interval averaged 100 micrograms/ml, which widely exceeds the known MIC of pipemidic acid against bacteria commonly causing urinary tract infections.

Single oral doses of ketoconazole (200 mg) or miconazole (250 mg) were given in a randomized cross-over study to 10 healthy volunteers. Ketoconazole with administered (i) after fasting (both brand 1 [Orion Pharmaceutical Co.] and brand 2 [Janssen Pharmaceutica] were tested), (ii) after a standardized meal (660 kilocalories; 2,772 kJ) (brand 1), and (iii) with 300 ml of orange juice (pH 3.8) (brand 1). Miconazole was administered after fasting. Venous blood samples for high-performance liquid chromatography determinations of ketoconazole and gas chromatographic analyses of miconazole were drawn periodically up to 24 h. The concentrations of ketoconazole in sera attained with the two brands were not statistically different. The peak concentrations of ketoconazole attained with brand 1 were 4.1 +/- 0.3 micrograms/ml (mean +/- standard error of the mean) after fasting, 2.3 +/- 0.3 micrograms/ml after the standardized meal (P less than 0.01), and 3.6 +/- 0.2 micrograms/ml with orange juice. The peak concentrations were reached in 1.4, 2.3 (P less than 0.05), and 1.8 h, respectively, whereas the areas under the serum concentration-time curves were 14.4 +/- 2.21, 8.6 +/- 1.33 (P less than 0.05), and 13.4 +/- 1.30 micrograms.h/ml, respectively. The half-lives (1.7 to 2 h) did not vary significantly among the different regimens. Compared with ketoconazole, oral absorption of miconazole was poor (peak concentration, 0.47 +/- 0.7 micrograms/ml; time to reach the peak concentration, 2.6 h; area under the serum concentration-time curve, 1.10 +/- 0.20 micrograms.h/ml).

Serum kinetics of metronidazole and tinidazole were compared in four separate randomized crossover studies. Single doses of each drug were given to healthy volunteers through intravenous infusion (500 mg over 20 min, six persons), by mouth (500 mg, nine persons), by rectum (1,000 mg, six persons), or intravaginally (500 mg, six persons). Concentrations of the unchanged drugs in serum, measured by high-pressure liquid chromatography, were similar after oral and intravenous administration, with mean peaks of 9.0 and 9.4 micrograms/ml for metronidazole and 7.5 and 10.1 micrograms/ml for tinidazole. Concentrations of tinidazole were significantly higher than those of metronidazole from 4 h onwards after intravenous infusion, and from 3 h onwards after administration by mouth. After rectal administrations, a significant difference was seen only at 48 h. After vaginal dosing, however, concentrations of metronidazole were significantly higher than those of tinidazole between 1.5 and 12 h. Bioavailability of either drug, calculated according to the formula (area under the curve for oral administration)/(area under the curve for infusion), was practically complete after oral administration and was poorer after rectal and especially vaginal administration. Whenever the parameters were calculable, the elimination half-life of tinidazole (range of means, 14.0 to 14.7 h) was significantly longer and total clearance (40.3 to 47.6 ml/min) was lower than the corresponding values of metronidazole (7.9 to 8.8 h and 71.8 to 80.1 ml/min, respectively).