Comparative drug disposition studies in mice, rats, dogs, and humans indicate that cephapirin, a new semisynthetic cephalosporin antibiotic that exhibits broad-spectrum antimicrobial activity, is metabolized to desacetylcephapirin in these species. Pharmacokinetic analyses of the concentrations of cephapirin and desacetylcephapirin in plasma and urine reveal that the rate and extent of deacetylation decreases from rodents to dogs to humans. The kinetic analyses also suggest that the kidney performs a role not only in the excretion but also in the metabolism of cephapirin to desacetylcephapirin.Cephapirin, sodium 7-(pyrid-4-yl-thioacetamido)cephalosporante ( Fig. 1), is a new semisynthetic 7-aminocephalosporanic acid derivative that exhibits a broad spectrum of antimicrobial activity (2,3,5) and in humans exhibits a similar pharmacokinetic profile to that of cephalothin (1). These results (1) were based on total bioactivity in serum, as determined by the cup-plate assay (6), and failed to take into account any possible differences in drug metabolism. In mice, rats, dogs, and humans, cephapirin has been shown to be metabolized to a bioactive desacetyl metabolite, and it has been suggested that the kidney performs a role not only in the excretion of the parent compound and desacetyl metabolite but also in the metabolism of cephapirin to desacetylcephapirin (B. E. Cabana and D. R. Van Harken, 5th Int. Congr., Pharmacol., San Francisco, Calif., Abstr. 209, p. 35, 1972 metabolism cages. In dogs, blood samples were taken from the saphenous vein by means of an intravenous (i.v.) catheter (Bardic, Intercath). The dogs were fasted overnight and hydrated (30 ml/kg) 15 to 30 min prior to drug administration. Continuous urine collection was achieved by means of Lucitecoated, stainless-steel cannulae surgically implanted within the bladder of the female dogs. The bladder cannulae were permanently implanted in dogs within 1 to 2 months of running the studies. The dogs had normal creatinine clearance (4 ml/min per kg) at the time of the study.Ten fasted, healthy male volunteers (mean weight, 66 kg) were employed for the human metabolic studies. The drug was administered by the i.v. route into the median cubital vein over a 5-min period. Blood specimens (20 ml) were drawn immediately before and at 5 min, 0.5, 1.0, 1.5, 2, 3, and 4 h after drug administration, and urine was collected at 1, 2, 4, and 6 h after drug administration. A water diuresis was maintained throughout the urine collection period by oral administration of 600 ml of tap water 20 min prior to drug administration and subsequent administration of 300 ml of water at 1 and 3 h after dosing.Blood specimens taken from the laboratory animals and men were placed in heparinized tubes (Vacutainers) and kept in an ice bath until centrifuged. Shortly thereafter, the blood specimens were spun down at approximately 1,000 x g in a refrigerated centrifuge (5°C), and the plasma samples were quickly frozen in a dry ice-acetone bath and kept frozen until bioassayed. The urine spe...

No abstract

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-

No abstract

The single-dose and steady-state pharmacokinetics of the angiotensin-converting enzyme (ACE) inhibitor fosinopril and its active diacid, fosinoprilat, were evaluated in 6 healthy volunteers and 12 patients with alcoholic cirrhosis. Fosinopril was administered at a dosage of 10 mg once daily for 14 days. Results in the two groups were similar, with no evidence of accumulation of fosinoprilat in hepatically impaired patients. Mean (+/- SD) maximum observed plasma concentrations of fosinoprilat in the healthy subjects were 112.0 +/- 67.2 ng/mL after the first dose and 144.1 +/- 61.7 ng/mL at steady-state. Corresponding values for the hepatically impaired patients were 111.4 +/- 40.1 ng/mL and 140.2 +/- 50.9 ng/mL. The area under the serum concentration versus time curve for healthy volunteers was 790.7 +/- 431.0 ng.hr/mL after the first dose and 940.3 +/- 400.4 ng.hr/mL at steady-state. Similar values were noted in hepatically impaired patients: 926.0 +/- 293.9 ng.hr/mL and 1,255.4 +/- 434.0 ng.hr/mL for first dose and steady-state, respectively. No statistically significant differences were detected in fosinoprilat pharmacokinetic values between healthy and hepatically impaired subjects. Absence of accumulation can be attributed to the dual route of elimination of fosinoprilat reported in previous studies. Renal excretion of fosinoprilat in hepatically impaired patients prevents increased accumulation. The present findings suggest that the starting dose of fosinopril used in hypertensive patients with normal renal and hepatic function can also be used in patients with hepatic impairment secondary to cirrhosis.