Sixteen healthy male volunteers participated in a randomized, balanced, three-way crossover study comparing the pharmacokinetics of cefmetazole, cefoxitin, and cefmetazole with probenecid pretreatment. Single 2-g doses of cefmetazole sodium and cefoxitin sodium were given intravenously as a 5-min infusion. Concentrations of cefmetazole and cefoxitin were determined by using a specific semiautomated highperformance liquid chromatographic method. Concentration-time profiles of cefmetazole and cefoxitin declined in a biexponential manner from peak levels. Compared with cefoxitin, cefmetazole had a significantly (P < 0.05) higher mean (± standard error of the mean) peak concentration in serum (290 ± 11 versus 244 ± 10 ,ig/ml), a longer terminal disposition half-life (1.50 ± 0.14 versus 0.81 ± 0.04 h), lower systemic clearance (111.7 ± 4.7 versus 279 ± 12 ml/min) and renal clearance (78.7 ± 4.3 versus 221 ± 14 ml/min) of intact drug, and a slightly smaller steady-state volume of distribution (10.3 ± 0.21 versus 12.8 ± 0.48 liters). Mean recoveries of cefmetazole and cefoxitin in urine were approximately 71 and 77%, respectively. Pretreatment of volunteers with probenecid (1 g orally) significantly (P < 0.05) increased concentrations of cefmetazole in serum 1 h after drug administration without significantly increasing maximum concentrations in serum. Mean areas under the concentration-time curve (466 ± 27 versus 295 + 13 ,ug h/ml) and terminal disposition half-lives (2.27 ± 0.13 versus 1.50 ± 0.14 h) of cefmetazole increased. Systemic clearance (72.1 ± 4.0 versus 111.7 ± 4.7 ml/min) and renal clearance (47.4 ± 4.0 versus 78.7 ± 4.3 ml/min) of intact antibiotic decreased. Mean recoveries (65.9 ± 3.7 versus 71.0 ± 3.2%) of intact cefmetazole in urine were not significantly (P > 0.05) different. Elimination of cefmetazole in urine was also significantly prolonged by probenecid, with substantial concentrations of cefmetazole ('20 ,g/ml) found in the 12-to 24-h urine collection for 14 of 16 volunteers. The results show that cefmetazole remains at clinically relevant concentrations (1 to 2 ,ug/ml) approximately twice as long as cefoxitin, that serum cefmetazole can be maintained longer at clinically significant concentrations with preadministration of probenecid, and that cefmetazole is partially eliminated by renal tubule secretion.Cefmetazole sodium is a semisynthetic derivative of cephamycin C (5) having a very broad antibacterial spectrum in vivo and in vitro, including the majority of clinically important gram-positive and gram-negative aerobic and anaerobic bacteria (4). The MICs of cefmetazole for a number of gram-positive and gram-negative organisms are in the range of 0.5 to 4.0 ,wg/ml (4,12). Clinical studies have confirmed its effectiveness, when administered parenterally, in the treatment of a number of infections (12) and as a prophylaxis for prevention of postsurgical wound infection (9).Pharmacokinetic studies in healthy human volunteers administered intravenous doses of cefmetazole sodium have been conducte...

The multiple dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 50 healthy male volunteers. Volunteers were randomized to receive intravenous normal saline placebo (n = 10), citrate vehicle placebo (n = 10), or 0.5 mg/kg/day (n = 6), 1.0 mg/kg/day (n = 6), 2.0 mg/kg/day (n = 6), 4.0 mg/kg/day (n = 6), or 6.0 mg/kg/day (n = 6) tirilazad mesylate in divided doses every 6 hours for 5 days, for a total of 21 doses. Drug was infused over 10 or 30 minutes. All tirilazad mesylate treatment groups and the citrate vehicle group had significantly more frequent and more intense pain at the injection site than did the saline group, but the pain intensity did not require interruption of dosing. Three episodes of clinical thrombophlebitis were observed. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, or renal function were apparent. Moderate and transient increases in serum alanine transaminase were observed in several subjects. In the 6.0 mg/kg/day group, 50% of the subjects exhibited increased alanine transaminase. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Tirilazad mesylate pharmacokinetics were linear over the dosage range studied. Steady state appeared to be achieved by the fifth day of dosing. After the last dose, a mean terminal half-life of 35 hours was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefpodoxime proxetil, a third generation, broad-spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of cefpodoxime proxetil were determined. Results from the single-dose study indicate that cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose-normalized AUC and Cmax, urinary recovery, and half-life between one or more of the higher-dose treatment groups and the 100-mg dosing group. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study.

The disposition of cefmetazole was studied in 25 subjects with various degrees of renal function after a 1,000-mg, constant-rate, 30-min intravenous infusion of cefmetazole sodium. In six subjects with creatinine clearance (CLCR) of >90 m/min per 1.73 m2 (group 1), the terminal elimination half-life (t4123) was 1.31 0.54 h (mean + standard deviation), cefmetazole total body clearance (CLp) was 132.8 25.1 ml/min per 1.73 m2, and volume of distribution at steady state was 0.165 ± 0.025 liter/kg. The fraction of dose excreted unchanged in the urine was 84.0% ± 26.1%. Subjects with CLcRs of 40 to 69 (group 2, n = 6) and 10 to 39 (group 3, n -6) ml/min per 1.73 m2 demonstrated prolongation of the tl12,3 (3.62 ± 1.06 and 5.93 ± 1.81 h, respectively) and significant reductions in cefmetazole CLp (52.8 ± 14.3 and 30.2 ± 10.2 ml/min per 1.73 m2, respectively), compared with group 1. In seven subjects on chronic hemodialysis (group 4) studied during an interdialytic period, the cefmetazole tl/2, was increased to 24.10 ± 8.12 h and the CLp was reduced to 6.8 ± 2.1 ml/min per 1.73 M2. Cefmetazole CLp correlated positively with CLCR (r = 0.951, P < 0.001): CLp = (1.181 CLCR) -0.287. The disposition of cefmetazole was also assessed in six group 4 subjects during an intradialytic period.The t1/2, during hemodialysis (2.09 ± 0.69 h) was significantly shorter than that observed during the interdialytic period. The hemodialysis clearance of cefmetazole was 86.1 ± 20.1 ml/min, and the fraction of cefmetazole removed during hemodialysis was 59.8% ± 5.9%. It is recommended that patients with renal insufficiency receive standard doses of cefmetazole at extended intervals and patients on maintenance hemodialysis receive standard doses after hemodialysis.Cefmetazole sodium is an investigational parenteral cephamycin antibiotic possessing activity against a broad spectrum of both gram-positive and gram-negative aerobic and anaerobic bacteria (3, 6, 11, 13). The MIC for 90% of strains of clinically important pathogens, such as Staphylococcus aureus, Escherichia coli, Klebsiella spp., Proteus mirabilis, Haemophilus influenzae, and Neisseria spp., ranges between 0.012 and 4 ,ug/ml (6). Clinical studies in humans have demonstrated efficacy in the treatment of various infections (15), including pneumonia (L.

The single-dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 47 healthy male subjects. Subjects were randomized to receive citrate vehicle (n = 12) or 0.25 mg/kg (n = 9), 0.5 mg/kg (n = 9), 1.0 mg/kg (n = 8), or 2.0 mg/kg (n = 9) tirilazad mesylate by 0.5-hour intravenous infusion. Injection site pain was observed with approximately equal frequency in both vehicle and tirilazad mesylate treatment groups. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, liver enzymes, or renal function were apparent. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Maximal plasma concentrations of tirilazad mesylate increased linearly with dose. Limited assay sensitivity at the lower two doses prevented determination of the dose proportionality of tirilazad area under the curve. The apparent elimination half-life at the higher doses was 3.7 hours. Clearance of tirilazad mesylate approached liver blood flow. Results indicate that intravenous infusions at these doses are well tolerated and devoid of glucocorticoid effects. Tirilazad mesylate appears to be efficiently cleared by the liver, and its pharmacokinetics are apparently linear over the dosage range studied.