Pharmacokinetics of cefmetazole in normal subjects and in patients with impaired renal function

Abstract

The pharmacokinetics of cefimetazole, a new cephamycin antibiotic, were examined after a 1-h intravenous drip infusion of 1 g to 5 healthy volunteers with normal renal function and 16 Group 1 was composed of five healthy volunteers with creatinine clearances of 95.6 to 155.6 ml/min. Group 2 was composed of four patients with creatinine clearances of 65.5 to 86.8 ml/min. In group 3 were four patients with creatinine clearances of 35.2 to 52.7 ml/ min. Group 4 had four patients with creatinine clearances of 10.2 to 24.8 ml/min. Group 5 was composed of four patients with creatinine clearances of 0 to 9.7 ml/min. Two patients in this group were being treated by hemodialysis twice weekly over 6 to 8 h.All of the subjects were given 1 g of cefmetazole dissolved in 200 ml of 5% dextrose-water. The drug was administered intravenously by drip infusion over a 1-h period. Blood samples were obtained just before infusion and 1, 2, 4, and 6 h after beginning the infusion. Urine specimens were collected from 0 to 2, 2 to 4, and 4 to 6 h. Because only two patients in group 5 were treated by periodic hemodialysis, they were studied between two dialysis sessions.Serum and urine samples were stored at -20°C until assayed. The concentrations of cefinetazole in serum and urine were determined by the thin cupplate method, with Micrococcus luteus ATCC 9341 as the test organism and heart infusion agar as the medium. For the measurement of serum concentrations, a standard solution series was prepared in pooled normal human serum. The assay range was from 200 to 7.8 itg/ml. For the measurement of urinary concentrations, the standard solution series of 20 to 1.25 ,ug/ ml was prepared with 1% phosphate buffer (pH 6.0). Urine was diluted with 1% phosphate buffer (pH 6.0) to give approximately a 5-,ug/ml sample solution. Table 1. The results demonstrated significant negative correlation between the serum concentration and the creatinine clearance (P < 0.05 at 1 h and P < 0.001 at 2, 4, and 6 h). As renal function declined, peak serum concentrations increased, i.e., the mean peak concentration in group 5 (severely impaired renal function) was 1.5 times that of normal subjects.

Disposition of cefmetazole in healthy volunteers and patients with impaired renal function

“…These differences may be a reflection of the shorter sampling time employed (only 6 h postdose), the use of different assay techniques (microbiological versus high-performance liquid chromatography), or the variability in the patient populations. Furthermore, a one-compartment model was used by Ohkawa et al (12) to fit the four postdose datum points, whereas our study utilized a two-compartment open model which provided a better fit of the plasma concentration-versus-time data for 24 of 25 subjects. Other differences include the measurement of a greater urinary recovery of intact drug in normal subjects (84%) than the previously reported mean of 69 to 71% (7,12).…”

“…All the subjects recovered with no sequelae. All abnormal laboratory tests (i.e., mild partial thromboplastin time elevation [n Ohkawa et al (12) evaluated the pharmacokinetics of cefmetazole in 21 subjects with normal (CLCR, >90 ml/min per 1.73 m2) and decreased (CLCR, 60 to 90, 30 to 59, and 10 to 29 ml/min per 1.73 m2) renal function. As in the present study, these investigators observed an unchanged V,s, a decreased CLp, and an increased t1/2, with declining renal function.…”

“…In patients with creatinine clearances (CLcRs) below 10 ml/min, the tl/2, of cefmetazole has been reported to be prolonged to approximately 15 h (12). The group, however, included nonhemodialysis and hemodialysis patients evaluated during an interdialytic period.…”

“…Single-dose intravenous pharmacokinetic studies in healthy human volunteers have reported mean peak concentration of 290 ,ug/ml in plasma after a 2-g bolus (7), mean terminal elimination half-lives (t1l2,s) ranging from approximately 0.8 to 1.8 h (7,12,14), and mean cumulative urinary recoveries of intact drug of 71% within 24 h of drug administration (7). In patients with creatinine clearances (CLcRs) below 10 ml/min, the tl/2, of cefmetazole has been reported to be prolonged to approximately 15 h (12).…”

Pharmacokinetics and dose proportionality of cefmetazole in healthy young and elderly volunteers

“…Cefmetazole pharmacokinetics have also been studied in patients with various degrees of renal insufficiency (13,20). In these patients, the elimination half-life of cefmetazole was found to increase progressively with decreasing renal function.…”