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 Fg/ml for metronidazole and 7.5 and 10.1 ,ug/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).Metronidazole and tinidazole have been used for some years as antiprotozoal drugs for prevention, and more recently for treatment, of infections with anaerobic bacteria (2, 3). The doses of these two drugs recommended for use against anaerobic infections are essentially the same and are much lower than those used for protozoal infections. There have been comprehensive comparisons of pharmacokinetics of metronidazole and tinidazole after oral ingestion (13, 14, 16), but there are not such studies related to intravenous, intrarectal, or intravaginal delivery, even though these compounds are also administered by these routes. The pharmacokinetics of metronidazole and tinidazole appeared to be different in isolated studies (4-6, 13a). The use of different assay procedures may have biased these results (10).This report deals with a comparison of study design of serum kinetics of metronidazole and tinidazole administered via oral, intravenous, rectal, or vaginal routes to healthy volunteers at doses currently recommended for anaerobic infections. The concentrations of both drugs were analyzed by a high-pressure liquid chromatography method specific for unchanged metronidazole and tinidazole.MATERIALS AND METHODS Subjects and general design. The study consisted of four separate experiments in which metronidazole and tinidazole were compared after intravenous, oral, rectal, or intravaginal administration. In each experiment, the volunteers were randomly assigned to receive either metronidazole or tinidazole...

Single oral doses of ketoconazole (200 mg) or miconazole (250 mg) were given in a randomized cross-over study to 10 healthy volunteers. Ketoconazole was 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 ,ug/ml (mean ± standard error of the mean) after fasting, 2.3 ± 0.3 p.g/ml after the standardized meal (P < 0.01), and 3.6 ± 0.2 pLg/ml with orange juice. The peak concentrations were reached in 1.4, 2.3 (P < 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 < 0.05), and 13.4 ± 1.30 xug.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 ,ug/ml; time to reach the peak concentration, 2.6 h; area under the serum concentration-time curve, 1.10 ± 0.20 pg.h/ml).Ketoconazole, a broad-spectrum antimycotic drug, is an imidazole derivative that is structurally related to miconazole; however, ketoconazole is more water soluble and better absorbed from the gastrointestinal tract than miconazole (2, 4). Since ketoconazole is a dibasic drug (pKa values, 6.51 and 2.94), the acidity of the stomach could play an important role in its absorption (2). It has been reported that an increase in gastric pH produced by cimetidine or antacids decreases absorption of ketoconazole (6). It has been recommended that this drug be taken with meals to attain best absorption (2). Ketoconazole is also rather lipid soluble (octanol-water partition coefficient [log P] = 3.73), suggesting that its absorption might be increased by lipidrich foods (2). These considerations led to this study of the effects of fasting and ingestion of a light breakfast or a large volume of orange juice on the absorption of ketoconazole in healthy volunteers. The absorption of miconazole was examined for comparison.MATERIALS AND METHODS Study design. Five females and five males, who were 22 to 26 years old (mean, 24 years) and weighed 55 to 70 kg (mean, 62 kg), participated in this study. These individuals were thoroughly informed of the purpose and design of the experiment and provided written consent. The following drug regimens, separated by intervals of 7 days, were used in a cross-over randomized manner:

Pharmacokinetics of conventional 80 mg tablets and two types of sustained-release (SR) tablets containing 120 and 200 mg of verapamil were compared cross-over in 12 healthy volunteers. Serum concentrations of verapamil and norverapamil were analyzed both after a single oral dose and at steady state after t.i.d. administration of conventional tablets and b.i.d. administration of SR tablets. After 120 mg SR tablets serum concentrations of verapamil usually remained below 100 ng/ml for 5 days. This inadequate bioavailability was caused by very slow absorption. The relative bioavailability of verapamil in 200 mg SR tablets was 93-96% as compared to the conventional tablets. After 200 mg X 2 and 80 mg X 3, the peak serum levels were about 300 and 190 ng/ml, respectively and the trough levels 123-153 and 52-56 ng/ml, respectively. The verapamil/norverapamil ratio varied from 0.69 to 0.84 after a single dose and from 0.8 to 0.93 at steady-state. By the 4th days of treatment, the accumulation ratios ranged between 1.75-2.07 and 1.30-1.75 for verapamil and norverapamil, respectively. For each preparation studied, the apparent Cltot of verapamil was significantly reduced at steady-state. These results show that 200 mg SR verapamil tablets fulfill the basic requirements of retard preparations allowing for twice or even once daily administration.

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