Microdialysis Study of Imipenem Distribution in the Intraperitoneal Fluid of Rats with or without Experimental Peritonitis

Abstract

The purpose of this study was to extend the use of microdialysis to the investigation of antibiotic distribution into the intraperitoneal fluid of rats with or without peritonitis. Microdialysis probes were inserted into the jugular vein and peritoneal cavity of control rats or rats with intra-abdominal sepsis (n ‫؍‬ 8 in each group) induced by cecal ligation and punctures. Imipenem (IPM) probe recoveries were determined in each rat by retrodialysis by drug. IPM was infused intravenously at a dose of 30 mg · kg ؊1 over 30 min, microdialysis samples were collected for 120 min, and IPM concentrations were determined by high-performance liquid chromatography. Intraperitoneal infection had no statistically significant effect on IPM clearance (11.9 ؎ 2.3 ml · min ؊1 · kg ؊1 in control rats versus 10.9 ؎ 2.1 ml · min ؊1 · kg ؊1 in rats with peritonitis) or the volume of distribution (296 ؎ 47 ml · kg ؊1 in control rats versus 310 ؎ 49 ml · kg ؊1 in rats with peritonitis). IPM concentration profiles in intraperitoneal fluid and blood were virtually superimposed in control rats, whereas in infected animals, the mean intraperitoneal IPM concentrations were apparently slightly lower than corresponding blood levels. However, the areas under the concentration-versus-time curve estimated in intraperitoneal fluid and blood were not significantly different in both groups, with the corresponding ratios close to unity (1.01 ؎ 0.19 and 0.89 ؎ 0.28 in control rats and rats with peritonitis, respectively). In conclusion, IPM distribution in intraperitoneal fluid is rapid and complete both in control rats and in rats with peritonitis.

Microdialysis Study of Imipenem Distribution in Skeletal Muscle and Lung Extracellular Fluids of Acinetobacter baumannii -Infected Rats

“…These results are consistent with data previously published by our group (7,10). Mean values of IPM blood pharmacokinetic parameters (clearance and volume of distribution) were close to those previously reported (10) but with more interindividual variability.…”

“…The present study confirms that even in the presence of infection, unbound IPM AUCs are not statistically different in blood, lung, and muscle, still consistent with theory. Similarly a lack of effect of infection on IPM distribution in peritoneal fluid was recently observed using an experimental model of peritonitis (7). Yet the present observation is not consistent with the findings of a previous study conducted with infected critically ill patients (16).…”

“…In fact because drug distribution in soft tissues such as muscle or lung is presumably governed by passive diffusion, unbound concentrations in blood and tissue ECFs should be identical at equilibrium (15). So in order to better address this more relevant issue, we have developed an approach using microdialysis both in tissues and in blood, allowing multiple direct determinations of concomitant unbound drug concentrations in blood and tissue ECFs (7,10,11). We have demonstrated that in agreement with basic pharmacokinetic concepts (15) and at least with IPM, free concentrations in blood and tissues were identical in various tissues or fluids such as lung (10), muscle (10), or peritoneal fluid (7) or in various experimental conditions including hypovolemia (11).…”

Microdialysis Study of Imipenem Distribution in the Peritoneal Fluid of Rats with Experimental Acute Pancreatitis

“…A pharmacokinetic model with peripheral elimination, consistent with the degradation of meropenem observed ex vivo in the PF of other patients, was developed to successfully fit the data. However, in a previous intraperitoneal-microdialysis study in rats, we observed that unbound imipenem concentration-versus-time profiles were almost always superimposed in blood and PF, both in control rats and in rats with an experimental model of peritonitis by cecal ligation and puncture (6). Although it should be confirmed experimentally, the same observation would most likely be made with the more stable meropenem (4).…”

“…Two CMA/20 probes (polycarbonate; membrane length, 10 mm; 20,000-Da cutoff; CMA microdialysis; Phymep, Paris, France) were inserted into the right jugular vein and into the central part of the pancreatic gland within the peritoneal cavity, respectively. The microdialysis study was conducted as previously described (6). After retrodialysis by drug period, in which probes were perfused with Ringer solution (Phymep, Paris, France) containing imipenem at 10 g ⅐ ml Ϫ1 (Tienam; Merck Sharp & DohmeChibret Laboratories), and a washout period, the rats received an intravenous infusion of imipenem at a dose of 30 mg ⅐ kg ) and directly analyzed as previously described (6).…”