Pharmacokinetics of aztreonam in patients with liver cirrhosis and ascites

Abstract

The pharmacokinetics of aztreonam were studied in six healthy male subjects (group I) and 12 male patients with post-hepatitis liver cirrhosis and ascites. Patients were allocated into two groups according to serum creatinine; group II included nine patients with serum creatinine. < or = 15 mg/L while group III included three patients with serum creatinine > 15 mg/L. Aztreonam 1 g was given as iv bolus injection. Aztreonam reached a peak concentration in the ascitic fluid (AF) of 6.2 +/- 2.3 mg/L at 4 h, and of 8.7 +/- 4.4 mg/L at 6 h in groups II and III respectively. The level of the drug in AF 24 h post-dosing was still higher than MIC90 for Enterobacteriaceae in most patients. The half-life of elimination from serum increased significantly (P > 0.001) from 1.82 +/- 0.14 h in group I to 6.6 +/- 2.1 h and to 8.87 +/- 0.2 h in groups II and III, respectively. Both the central and the terminal volumes of distribution were higher in cirrhotic patients than in healthy volunteers. Liver cirrhosis and ascites resulted in a significant increase (P < 0.001) of the total body clearance (Cl) of aztreonam from 84 +/- 8 mL/h/kg in group I to 209 +/- 87 mL/h/kg in group II. However, the concomitant association of mild renal impairment in group III abolished this increase; Cl in group III was 122 +/- 50 mL/h/kg. The AUC0-infinity serum was 137.5 +/- 12.2, 78.5 +/- 24.9 and 151 +/- 42 mg.h/L in groups I, II and II, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphatidylcholine-dependent protein kinase C activation. Effects of cis-fatty acid and diacylglycerol on synergism, autophosphorylation and Ca2+-dependency

“…Protein kinase C was recently shown to be activated additively or synergistically by cis-fatty acid and DAG in the presence of PS [12][13][14][15][16][17]. Our study further showed that, among the protein kinase C subtypes, type III is most sensitive to the synergistic activation mode [17].…”

“…DAG stimulates the PS/Ca2+-dependent protein kinase C activity and decreases the requirement for Ca2+ to the micromolar range [4]. cis-Fatty acid further enhances the PS/DAG-dependent activation [12,[14][15][16][17]. This modulatory effect of cis-fatty acid, which is dependent on the presence of DAG, is two-fold: induction of a strong synergistic activation of protein kinase C, particularly type III, and nullifying the requirement of Ca2+ for the activation [16,17].…”

“…Protein kinase C has been shown to be autophosphorylated when it is activated by PS, DAG and Ca2" [30][31][32][33]. On the other hand, El Touny et al [12] have shown that autophosphorylation of platelet protein kinase C is negligible when it is activated by oleic acid. These observations suggest that there is a distinct difference between active states of protein kinase C induced by PS/DAG/Ca2l and cis-fatty acid.…”

“…In addition to the DAG-dependent activation mechanism, cisunsaturated fatty acid has been shown to activate protein kinase C in the absence of phospholipids and DAG [5][6][7][8][9][10][11]. It has been further demonstrated that cis-fatty acid preferentially activates soluble protein kinase C, and it was suggested that the site of action of cis-fatty acid is not in the membrane, but rather in the cytosol [12].…”

Clinical Pharmacokinetics of Aztreonam

“…In one study the presence of ascites influenced plasma pharmacokinetics of aztreonam such that a 3-compartment model gave a better fit than a 2-compartment model (EI Touny et al 1992). The maximal concentration of aztreonam in ascitic fluid occurred about 6 hours after intravenous bolus administration of the drug to 12 patients with cirrhosis of the liver and ascites.…”