Ceforanide (BL-S786R) is a new, broad-spectrum, parenteral cephalosporin. Pharmacokinetic properties weredetermined in rats (100 mg/kg), rabbits (30 mg/ kg), dogs (25 mg/kg), and humans (2 g or 30 mg/kg) and compared with equivalent single doses of cefazolin. Plasma half-lives for ceforanide and cefazolin were 1.1 and 0.5 h in the rat, 5 and 0.3 h in the rabbit, 1 and 0.8 h in the dog, and 2.6 and 2 h in humans, respectively. The slower elimination of ceforanide, as reflected by longer plasma half-life, larger area under the curve, and peak plasma concentrations, was due to slower body and renal clearances. The apparent volumes of distribution of ceforanide and cefazolin were comparable. Rats, dogs, and humans excreted 80 to 100% of the ceforanide dose in the 0-to 24-h urine; rabbits excreted only 50%. Tubular secretion constituted 50% of ceforanide renal excretion in rabbits, dogs, and humans and 90% in rats; the remainder was excreted by glomerular filtration. There was no apparent correlation between the extent of tubular secretion and degree of plasma protein binding in different species. There was no ignificant pharmacokinetic interaction between ceforanide and amikacin in the rat. The slower elimination kinetics of ceforanide are indicative of the potential for a longer dosing interval and more effective antibiotic therapy as compared with available cephalosporins.Ceforanide is a new, parenteral cephalosporin with a broad spectrum of antibiotic activity (7 metabolized before elimination, and renal excretion is the major elimination route. The usual adult dose is 0.5 to 1.0 g administred twice daily. Since combination cephalosporin-aminoglycoside therapy is employed clinically, the potential for pharmacokinetic interaction of ceforanide and amikacin was also evaluated in rats. This paper reports the renal-plasma pharmacokinetics of ceforanide and cefazolin in laboratory animals (rats, rabbits, and dogs) and humans. MATERIALS AND METHODSCephalosporins. Ceforanide (BL-S786R), the Llysine salt of 7-(2-amino-methylphenylacetamido)-3-(1-carboxymethyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid, was synthesized at and supplied by Bristol Laboratories. Cefazolin, the sodium salt of 3-

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Bleomycin kinetics were determined in 14 children after intravenous bolus and prolonged infusion doses. Plasma and urine bleomycin concentrations were determined by radioimmunoassay. After intravenous bolus, bleomycin concentrations were adequately described by a two-compartment open model with a mean t1/2 alpha and t1/2 beta of 0.3 +/- 0.1 and 3.2 +/- 0.7 hr (mean +/- SEM). Volume of the central compartment and volume of distribution at steady-state (Vss) were 4.3 +/- 0.5 and 9.9 +/- 1.1 l/m2. Total plasma (CLT) and renal (CLR) clearance were 51.8 +/- 6.1 and 33.5 +/- 2.4 ml/min/m2. Three intravenous bolus courses were given to two patients who received more than four courses of cisplatin (greater than 300 mg/m2); CLT and CLR for these courses were 18.0 +/- 3.3 and 8.2 ml/min/m2. Conversely, children under 3 yr old eliminated bleomycin more rapidly than older children. Decline in bleomycin concentrations after seven 24- or 48-hr intravenous infusions was described by a one-compartment model. Mean values for plasma t1/2, Vss, CLT, and CLR were 2.1 +/- 0.1 hr, 11.0 +/- 2.6 l/m2, 57.1 +/- 13.5 ml/min/m2, and 33.2 +/- 6.4 ml/min/m2. One patient received his bleomycin infusion when ureteral obstruction was present; CLT and CLR for this course were 4.8 and 4.1 ml/min/m2. These data indicate that young children eliminate bleomycin more rapidly than older children and that children with impaired renal function may have prolonged elevations in plasma concentration due to reduced bleomycin clearance. Bleomycin disposition in older children is as in adults.

Phosphanilic acid is an antibacterial agent with a mode of action and antibacterial spectrum similar to those of sulfamethoxazole, with the exception that it has potent antipseudomonal activity. Bioavailability studies in rats (50, 300, and 600 mg/kg, oral and subcutaneous), dogs (50, 150, and 450 mg/kg, oral and intravenous infusion), and humans (400 and 800 mg, oral) showed that the extent of oral absorption of potassium phosphanilate was low. The bioavailability, calculated by comparing the oral values for area under the plasma concentration curve with those for the respective parenteral doses, was 10% for rats and 45 (50 and 150 mg/kg) and 19% (450 mg/kg) for dogs. The 24-h urinary recovery also confirmed the low oral bioavailability, i.e., rat, 13 (oral) and 75% (subcutaneous); dog, 15 to 29 (oral) and 87% (intravenous) of the dose. Plasma levels and urinary recovery (4%, oral) were low and variable in humans. The poor absorption of oral doses may be due to drug precipitation in the stomach, low permeability of the soluble species due to extensive in situ ionization (pKa, 1.8 to 2) in the intestine, or first-pass metabolism to N-acetylphosphanilic acid. The plasma t1/2 values after parenteral administration were 0.3 h in rats and 1.3 h in dogs. Although the lack of adequate blood levels of phosphanilic acid after oral administration in humans precludes the use of this compound for treatment of systemic infections, the sustained urinary concentration at levels severalfold higher than the minimal inhibitory concentration (1 ,ug/ml) for at least 10 h postdose was indicative of the therapeutic usefulness in urinary tract infections.