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The effect of cimetidine or ranitidine administration on responses to single and multiple doses of nifedipine were studied in 11 subjects who received cimetidine (300 mg q.i.d.) and 12 who received ranitidine (150 mg b.i.d.) in combination with nifedipine. After single doses of nifedipine, cimetidine decreased apparent oral clearance (dose/AUC) from 66 +/- 32 L/hr to 33 +/- 14 L/hr (p less than 0.01); elimination half-life increased from 4.0 +/- 2.2 to 4.9 +/- 2.9 hours (p less than 0.07). Increases in heart rate were greater (26 +/- 13 vs 13 +/- 11 beats/min standing; 19 +/- 11 vs 9 +/- 9 beats/min supine) and lasted longer than after nifedipine alone. Hypotensive effects were similar (10 +/- 7 mm Hg decrease vs 9 +/- 9 mm Hg). During nifedipine multiple-dose administration, cimetidine decreased the apparent oral clearance from 76 +/- 39 to 43 +/- 20 L/hr (p less than 0.01). Blood pressure responses were not altered by cimetidine but heart rate increased more (18 +/- 9 vs 9 +/- 9 beats/min supine; 18 +/- 13 vs 13 +/- 14 beats/min standing). Ranitidine coadministration did not alter nifedipine elimination or dynamic responses. During administration of nifedipine alone, the ratio of oral clearances (multiple to single doses) was 1.1 +/- 0.5. Thus (1) cimetidine but not ranitidine alters responses to nifedipine and (2) nifedipine kinetics do not differ between single- vs multiple-dose conditions.

This study determined the pharmacokinetic disposition of cefonicid. A single dose of 7.5 mg/kg of body weight was administered to five healthy volunteers as a 5-min intravenous infusion. Multiple plasma and urine samples were collected for 48 h. Peak plasma concentrations ranged from 95 to 156 micrograms/ml and fell slowly (mean plasma half-life, 4.4 +/- 0.8 h), so that levels after 12 h were in the range of 6 to 12 micrograms/ml. Urinary concentrations were high but variable and ranged from 100 to 1,000 micrograms/ml for the first 12 h after the dose and averaged 84 micrograms/ml between 12 and 24 h. Plasma and renal clearances were 0.32 +/- 0.06 and 0.29 +/- 0.05 ml/min per kg, respectively. An average of 88 +/- 6% of the dose was excreted unchanged in the urine over 48 h. The mean steady-state volume of distribution was found to be 0.11 +/- 0.01 liters/kg.

The bioavailability of two commercial preparations of chlorthalidone was studied in healthy male subjects. Reference solutions/suspensions for the two products were chlorthalidone dissolved in a solution of water-polyethylene glycol and a solution/suspension of chlorthalidone. Bioavailability of the chlorthalidone in water-polyethylene glycol solution was significantly reduced in comparison to one of the commercial preparations, and trends in the data suggested that it was less well absorbed than either the chlorthalidone in water solution/suspension or the other commercial preparation of chlorthalidone. These data, together with previous reports indicating that polyethylene glycol may retard the absorption of some drugs in vitro, suggest that this compound should not be used to aid dissolution of drug in a reference standard for bioavailability investigations.