Pharmacokinetics of moxalactam in patients with renal insufficiency

The pharmacokinetics of cefoperazone, cefotaxime, and moxalactam were compared in a cross-over randomized study in 10 healthy volunteers. Each subject received 1.0 g of the three drugs by bolus intravenous injection over 3 min. Serum and urine concentrations were assayed by a microbiological method and in addition by high-pressure liquid chromatography (HPLC) for cefotaxime in five subjects. Maximal concentrations in serum 5 min after the injection were 163 ± 40.3 mg/liter for cefoperazone, 86.1 ± 19.0 mg/liter for cefotaxime, and 95.5 ± 21.1 mg/liter for moxalactam. After 12 h, 1.2 ± 1.4 mg of cefoperazone per liter and 1.8 ± 0.9 mg of moxalactam per liter could still be measured. Eight hours after the administration of cefotaxime, serum concentrations were below the detection limit of 0.3 mg/liter in most subjects. By HPLC analysis, the mean maximal concentration of desacetyl cefotaxime was 16.6 ± 10.5 mg/liter 5 min after application; the metabolite exceeded the serum concentration of the parent compound after 1 to 2 h. Relevant pharmacokinetic parameters were calculated, using two-and three-compartment models. The terminal half-life was 144.1 ± 37.3 min for cefoperazone, 76.1 ± 32.0 min for cefotaxime, and 272.4 ± 114.1 min for moxalactam. The apparent volume of distribution corresponded to the extracellular volume. Only 25.1 ± 8% of cefoperazone could be detected in urine compared with 53.3 ± 8.1% of cefotaxime and 61.0 ± 9.2% of moxalactam in 24 h. A total of 89.6 ± 11.4% of the cefotaxime dose could be recovered by HPLC in urine, 60.6 ± 7.7% as cefotaxime and 29.1 ± 7.0% as desacetyl cefotaxime.Cefoperazone, cefotaxime, and moxalactam are three newly developed cephalosporins with a high level of resistance to P-lactamase hydrolysis and a broad range of antibacterial action (13,18,28). The purpose of the present study was to compare the pharmacokinetics of these cephalosporins after a single intravenous (i.v.) bolus injection. MATERIALS AND METHODSSubjects. Ten healthy volunteers, five males and five females, 21 to 51 years of age (mean, 32 years of age), 44 to 82 kg (mean, 66.7 kg), participated as test subjects. Informed written consent was obtained from each subject.Administration of antibiotics. Cefoperazone sodium (Ch.-BI 130) was supplied by Pfizer GmbH, Karlsruhe, Federal Republic of Germany; moxalactam disodium (Ch.-BI-4473-9C) by E. Lilly Giessen, and cefotaxime (batch no. 100 N31) by Hoechst AG, Frankfurt, Federal Republic of Germany. The compounds were reconstituted in sterile water just before administration. Each subject received 1.0 g of cefoperazone, cefotaxime, and moxalactam by an i.v. injection over 3 min. The antibiotics were given by random allotment with a 1-to 2-week interval between the injections.Sampling. Blood samples were taken over 12 h: before injection; after 5, 10, 20, 30, and 45 min; and after 1, 1.5, 2, 3, 4, 6, 8, and 12 h. Blood specimens were centrifuged at 4°C after clotting at room temperature. Urine was collected 0 to 3, 3 to 6, 6 to 12, and 12 to 24 h after dosage.An...

Section: Methodssupporting

confidence: 76%

Comparative pharmacokinetics of cefoperazone, cefotaxime, and moxalactam

Kemmerich¹,

Lode²,

Belmega³

et al. 1983

“…Thus, the Varea of cefotiam is considerably larger than that of cefazolin (0.14 liters/kg) (4) and is comparable to that of moxalactam (0.34 liters/kg) (8).…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of cefotiam in patients with impaired renal function and in those undergoing hemodialysis

Konishi¹,

Ozawa²

1984

The pharmacokinetics of cefotiam were studied after a single intravenous 1.0-g dose to 18 subjects grouped according to their creatinine clearances (CLCR); CLCR was above 75, 75 to 20, and below 20 ml/min per 1.73 mn2 in groups 1, 2, and 3, respectively. Cefotiam obeyed two-compartment Eighteen adult male and female subjects with renal function ranging from normal to functionally anephric were studied after written, informed consent was obtained. None had any clinical evidence of congestive heart failure or hepatic dysfunction. Endogenous creatinine clearance (CLCR) was determined for urine collected over a 24-h period. For purposes of comparison, the subjects were divided arbitrarily into three groups: group 1, CLCR greater than 75 ml/min per 1.73 i2; group 2, CLCR 20 to 75 ml/min per 1.73 m2; group 3, CLCR < 20 ml/min per 1.73 i2. Five of the subjects in group 3 were being supported by maintenance hemodialysis and were studied between dialysis. CLCR in these five patients was calculated based on the average of the serum creatinine concentration at the beginning and at the end of urine collection (9).Procedure. Each patient received 1.0 g of cefotiam dissolved in 20 ml of physiological saline intravenously over exactly 5 min. Blood samples for serum cefotiam levels were obtained 10, 20, and 30 min as well as 1, 2, 4, 6, 12, and 24 h after injection. Urine samples were collected during time intervals of 0 to 6 h and 6 to 24 h. Serum and urine samples were stored at -70°C until assayed.Assay. Serum and urinary cefotiam concentrations were * Corresponding author.determined by the cylinder-plate technique, using Proteus mirabilis ATCC 21100 as the test organism grown in DST agar medium (Oxoid Ltd., London, England) (pH 8.0) (7). Serum and urine standards were prepared in normal pooled sera and phosphate buffer at pH 7.0. As low as 0.1 p.g of cefotiam per ml in 0.1 M phosphate buffer (pH 7.0) or 0.2 ,ug/ml in human serum specimens could be measured by this method. The within-day coefficients of variation were 3.4 and 2.2% for the low and high assay extremes, whereas the between-day coefficients of variation were 8.0 and 9.1%, respectively. All assays were done in triplicate and were in excellent agreement. Pharmacokinetic analysis. The cefotiam levels in serum after intravenous administration were described in terms of two-compartment open model, and the individual serum level profiles were fitted to a bi-exponential function of the form of equation: C = A x e-" + B x e-',, in which C is the concentration of antibiotic in serum at time (t) post-dosing; a and 3 are the rate constants (slopes) governing the distribution and elimination phases of drug loss from serum, respectively; and A and B are the intercepts of elimination slopes a and f with ordinate (13). Pharmacokinetic analysis was performed by using an improved version of the computer program reported by Ouchida et al. (11)

“…Compared with other cephalosporins, ceftizoxime had a relatively long t1,2 similar to those of cefazolin, cefoperazone, and moxalactam in normal subjects (1,2,13,15). The drug accumulated as do cefazolin and moxalactam (to a greater degree than cefamandole, cefoxitin, and cefotaxime) in patients with renal insufficiency (2,4,5,9,10). Although there is no report concerning renal, hepatic, or hematological toxicity, dosage adjustment might be necessary in patients with severe renal dysfunction to avoid excessive serum levels.…”

Section: Discussionmentioning

confidence: 99%

Elimination kinetics of ceftizoxime in humans with and without renal insufficiency

Ohkawa¹,

Okasho²,

Sugata³

et al. 1982

The pharmacokinetics of a single 500-mg intramuscular dose of ceftizoxime were studied in 11 healthy adult volunteers and in 22 patients with various degrees of renal dysfunction. The mean serum half-life of ceftizoxime was 1.44 h in normal subjects and 30.2 h in hemodialysis patients. A significant correlation (P less than 0.001) between the elimination rate constant of ceftizoxime and creatinine clearance was demonstrated. The mean urinary recovery in normal subjects was 75.6% within 6 h of dosage; recovery decreased progressively with reduced renal function.