Microdialysis Study of Imipenem Distribution in Skeletal Muscle and Lung Extracellular Fluids of Noninfected Rats

Abstract

The aim of this study was to investigate the imipenem distribution in muscle and lung interstitial fluids by microdialysis in rats and to compare the free concentrations in tissue with the free concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle, and lung. Imipenem recoveries in these three media were determined in each rat by retrodialysis by drug period before drug administration. Imipenem was infused intravenously at a dose of 120 mg · kg ؊1 over 30 min, and microdialysis samples were collected for 150 min. The whole study was conducted with nonhydrated rats (n ‫؍‬ 4) and hydrated rats (n ‫؍‬ 6) while the animals were under isoflurane anesthesia. The decay of free concentrations in blood, muscle, and lung with time were monoexponential; and the concentration profiles in these three media were virtually superimposed in both groups. Accordingly, the ratios of the area under the curve (AUC) for tissue (muscle or lung) to the AUC for blood were always virtually equal to 1. Compared to values previously determined with awake rats, clearance was reduced by 2 and 1.5 in nonhydrated and hydrated rats, respectively, but the volume of distribution was unchanged. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

“…In fact, this has been confirmed experimentally on many occasions, in particular, during experimental microdialysis studies conducted by several groups with rats and various antibiotics, including piperacillin (4, 26); ceftriaxone (18); pazufloxacin, ciprofloxacin, ofloxacin, and ceftazidime (1); imipenem (24); and amoxicillin (25). For similar reasons, ECF concentrations should be identical in various soft tissues, which in fact constitutes the rationale for conducting microdialysis studies with muscle tissue, which is more easily accessible, although possibly less relevant, than lung tissue.…”

“…On the day before the experiment, the rats were anesthetized by isoflurane (Forene, Abbot, Rungis, France) inhalation (23,24). Polyethylene cannulas were inserted into the left femoral vein and artery for drug administration and blood sampling, and two CMA/20 probes (polycarbonate; membrane length, 10 mm; CMA microdialysis; Phymep, Paris, France) were inserted into the right jugular vein and the right hind leg muscle as described previously (24). The rats were allowed to recover to a conscious state.…”

“…IPM analysis. Analysis of IPM in the dialysates was performed by an adaptation of a previously described HPLC assay (11,12,24). Standard curves were prepared with IPM in water at concentrations ranging from 0.78 to 50 g · ml Ϫ1 .…”

“…Muscle tissue has frequently been chosen because it is relatively accessible and the concentrations in muscle tissue seem to be a reasonable predictor of the unbound concentrations in more therapeutically relevant tissues, such as lung tissue (7,20,21). A microdialysis study conducted by our group with healthy rats has recently shown that free IPM concentrations in muscle tissue, lung tissue, and blood are virtually identical at any time postdosing (24).…”

“…Experiments with animals allow better control of these multiple interfering parameters, and many microdialysis studies have also been conducted with rats to investigate the distribution of amino ␤-lactams in muscle (4,7,18,20,21,22,24,25). Muscle tissue has frequently been chosen because it is relatively accessible and the concentrations in muscle tissue seem to be a reasonable predictor of the unbound concentrations in more therapeutically relevant tissues, such as lung tissue (7,20,21).…”