cefpiramide and Cholestasis

Cefpiramide is a new parenteral cephalosporin mainly excreted in the bile. Eight patients with cholestasis and 11 healthy subjects received a single 1 g i.v. dose. Cefpiramide concentrations in plasma and urine were measured by h.p.l.c. and plasma binding was determined by ultrafiltration. Total clearance of cefpiramide (mean +/- s.d.) was 15.5 +/- 7.1 ml min-1 in patients and 25.6 +/- 4.6 ml min-1 in healthy subjects. As a result, the terminal elimination half-life was longer in patients (12.0 +/- 2.9 h vs 5.3 +/- 0.9 h). Owing to impaired biliary elimination of cefpiramide in cholestasis, the urinary recovery of unchanged drug in patients was about five times greater than in healthy subjects (85.1 +/- 10.3% vs 16.2 +/- 3.9%). Plasma binding was significantly lower in cholestasis (fu = 0.23 +/- 0.13 vs 0.02 +/- 0.004 in healthy subjects). Accordingly, the dosage regimen of cefpiramide should be modified in patients with cholestasis.

Topics: Aged; Aged, 80 and over; Blood Proteins; Cephalosporins; Cholestasis; Chromatography, High Pressure Liquid; Female; Humans; Injections, Intravenous; Liver Function Tests; Male; Middle Aged; Protein Binding

The mechanism of the diminished biliary clearance of cefpiramide (CPM) in rats with obstructive jaundice (OJ) was investigated by using isolated hepatocytes. The kinetics of CPM uptake by hepatocytes isolated from normal rats and rats with OJ could be explained by the combination of saturable carrier-mediated and nonsaturable first-order rate processes. The maximum uptake rate (Vmax) of the carrier-mediated process was significantly decreased in OJ, compared with normal hepatocytes, while the Michaelis constant (Km) and the first-order rate constant (kd) were not significantly different. This result indicated that the number of CPM transport carriers was decreased in OJ hepatocytes. Further, no CPM uptake occurred from the serum of OJ rats into normal hepatocytes. Partial recovery of CPM uptake after treatment of OJ serum with activated charcoal suggested the accumulation of inhibitors of CPM uptake in OJ serum.

Topics: Animals; Biological Transport; Cephalosporins; Cholestasis; In Vitro Techniques; Liver; Male; Metabolic Clearance Rate; Rats

Changes in the mode of drug excretion in obstructive jaundice (OJ) were investigated in rats with experimentally induced OJ using a non-metabolized, highly-biliary-excreted antibiotic, cefpiramide (CPM). In OJ rats, biliary excretion of the drug was markedly diminished, while the urinary excretion was increased. The change in the mode of CPM excretion was examined in detail. It seems that the biliary excretion of CPM was decreased owing to the diminished biliary clearance in OJ rats. On the other hand, CPM binding to plasma proteins was decreased in the disease state. This change in the protein binding would be due to both the decreased albumin concentration and the accumulation of binding inhibitors in the plasma of diseased rats, and the decreased protein binding would be related not only to the increase in the volume of distribution but also to the increase in the renal clearance.

Topics: Animals; Bile; Blood Proteins; Cephalosporins; Cholestasis; In Vitro Techniques; Kidney Cortex; Male; Metabolic Clearance Rate; Protein Binding; Rats; Rats, Inbred Strains

The effectiveness of antibiotics on biliary tract infections should be evaluated strictly by bacteriological findings rather than clinical results. In this report, the bacteria counts and drug excretion in bile were studied in 4 cases with obstructive jaundice. All patients received cefpiramide (CPM) (1.0 g) by the intravenous administration; before and at 1, 2, 4, 8 and 24 hours after injection, bile samples were taken to measure the CPM concentration (by bioassay) and bacteria counts (by plate count and uricult method). Case 1: After Soupault's operation. The highest peak of CPM excretion in bile was seen after 2 hours; bacteria counts (plate count) were decreased and/or abolished after 4 hours. Case 2: On day 25 after PTCD. CPM showed the highest peak after 1 hour, bacteria counts fell between 3 approximately 5 hours. Case 3: 4 months after PTCD. S. faecalis and Streptococcus were gradually diminished but E. cloacae (MIC greater than 100) was almost unchanged. Case 4: Cholangitis with T-tube. No change was seen in A. anitratum though CPM concentration was 830 micrograms/ml. However by the uricult method, bacteria counts decreased from 10(7) to 10(4) on CLED medium, and to 10(3) on MacConkey medium. From these results, the bacteria counts in the bile were correlated to the CPM concentrations 2 hours after it's peak. It was speculated that the decease of bacteria counts reflected the theoretical antibacterial activity.

Topics: Aged; Bacterial Infections; Bacteriological Techniques; Bile; Biliary Tract Diseases; Cephalosporins; Cholestasis; Drug Evaluation; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Male; Middle Aged