Pulmonary uptake of bupivacaine in isolated perfused rat lung

Abstract

The ability of rat lung to remove the local anaesthetic drug bupivacaine from the blood was studied in isolated organs which were perfused either in an open (single-pass mode) or in a closed system (recirculating medium).

Isolated perfused rat lungs exhibited a very low capacity to metabolize bupivacaine within 3 h during which the drug circulated continuously through the organ. The clearance values differed only by 0.2 ml/min from the control parameters in sham perfusions. The calculated extraction ratio was 0.2% and the elimination half-life was about 210 min. The volume of distribution of bupivacaine was 133 ml which remarkably surmounted the reference values obtained for sham perfusions.

The distribution of bupivacaine into the pulmonary tissue was investigated applying the multiple indicator dilution technique to isolated lungs perfused in the single-pass mode. The mean elimination time of model compounds for distribution into the intravascular space, ¹⁴C-inulin, and the total water space, ³H-water, were 68 and 75 s at a flow rate of 6 ml/min. The volume of distribution was 5.9 ml for inulin and 6.5 ml for water. The mean transit time for concomitantly injected bupivacaine was 221 s and the volume of distribution was 14.4 ml. The respective parameters of sham perfusions performed without an isolated organ were substantially lower, i.e. mean elimination time 50, 50 and 61 s and distribution volume 4.9, 5.0 and 6.1 ml for inulin, water and bupivacaine.

The volume of distribution during single-pass contact of bupivacaine to lung was not substantially influenced by an increase of the flow rate from 6 to 9 and 12 ml/min whereas the mean transit time dropped from 221 to 121 and 108 s, respectively. These results support the assumption that bupivacaine is extensively retained by the pulmonary tissue and that elimination of bupivacaine by metabolism can be neglegted for lung.

The hemodynamic parameters of bronchiolar perfusion in the artificially perfused lung were determined using two fluorochrome-labeled macromolecular proteins, i.e. fluorescein-isothiocyanate (FITC)- and lissamine-rhodamine-B 200 (RB 200)-labeled globulin. After 10 min of perfusion at a flow rate of 12 ml/min in the closed system an area of 10.8070 of the peribronchiolar tissue area contained the dye-label FITC. A very similar index (10.1%) of dye-coloured capillaries was obtained when the lungs of anaesthetized rats were examined 10 min after intravenous injection of the fluorochrome into the pulmonary artery in vivo. In isolated perfused rat lungs receiving both FITC and RB 200 59.5% of FITC-labeled capillaries were reached by the second fluorochrome within 2 s. This fraction accounted for 93.3% after 10 s of circulation time. This proves that isolated rat lungs were well perfused in vitro.