Ceftazidime disposition after an intravenous dose of 50 mg/kg infused over 20 min was followed in 10 subjects with cystic fibrosis (CF) hospitalized with acute pulmonary exacerbations and in 10 healthy subjects. Serum ceftazidime elimination t 1/2 decreased from 105.3 +/- 12.4 min (mean +/- SD) in controls to 90.0 +/- 11.1 min in subjects with CF. Calculated distribution volumes were both larger in subjects with CF. When normalized for body surface area, total body clearance (Cl) was 41.9% greater in the CF group (142.4 +/- 16.9 and 100.5 +/- 10.3 ml/min/1.73 m2). Normalization for body weight revealed 64.8% greater Cl in subjects with CF. Fraction of dose recovered in urine was of the same order for each group, while renal clearance (ClR) was 40.9% greater in the subjects with CF (130.1 +/- 11.4 and 92.7 +/- 11.6 ml/min/1.73 m2). Five subjects with CF were restudied while infection-free 119 to 219 days after the original study day. With the exception of a 10% increase in the volume of distribution at steady state while infection-free, kinetic parameters were much the same. No changes in Cl or ClR were evident from one study day to the next. Acute pulmonary infection does not appear to alter ceftazidime clearance in CF. The mechanism underlying increased ceftazidime Cl and ClR in CF is not apparent from the present data.
The temporal aspects of theophylline disposition are of interest, as there are predictable time-dependent fluctuations in the pulmonary function of patients with asthma and theophylline serum concentrations may vary throughout a 24-hour period. We studied the extent to which there are significant temporal changes in theophylline kinetics and the relative contribution of distribution, metabolism, and excretion to this phenomenon. Eight healthy men received an intravenous dose (6 mg/kg) of theophylline at 8 AM and 8 PM at 1-week intervals. Serum and urine were analyzed for theophylline and its three major metabolites by HPLC. Distribution volumes and total body and nonrenal clearances showed no differences between morning and evening dosing. The elimination rate was 12% greater after morning dosing. Renal clearance was 24% greater after morning dosing and was accompanied by an increased excretion fraction of unchanged theophylline. Based on total urinary metabolite excretion and the metabolite serum AUCs, there was no evidence of time-dependent variation in theophylline biotransformation. Although theophylline renal clearance is greater after morning dosing, it is only a small fraction of the overall drug elimination and does not change the total body clearance after morning or evening dosing.
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