THE PHARMACOKINETIC CHANGE OF LIDOCAINE BY CATECHOLAMINES USING ISOLATED-PERFUSED RAT-LIVER (IPRL)

We hypothesized that changes in the pharmacokinetics of lidocaine migh t reveal changes in portal circulation induced by catecholamines. Isol ated perfused rat Liver (IPRL) was selected as an experimental model, since experimental conditions in this model could be regulated. The li ver was perfused with a recirculating system at a constant flow rate o f 20 ml/min. Two milligrams of lidocaine was administered along with o ne of three drugs, dopamine, norepinephrine or adenosine triphosphate. The fractional transfer rate constants, k(21) and k(12), from medium to liver and Liver to medium, respectively, and k(e), the elimination rate constant, were calculated using a two-compartment model with the SAAM II(TM) program. Curves of decay of lidocaine from the recirculati ng medium consisted of a fast and a slow component. Norepinephrine and high-dose dopamine significantly increased k(12), while low-dose dopa mine significantly increased k(21) and k(e) compared with control valu es. Thus, norepinephrine and high-dose dopamine increased lidocaine tr ansfer rate from liver to medium, while low-dose dopamine increased th e transfer rate from medium to Liver and the rate of elimination from liver. These findings suggest that norepinephrine and high-dose dopami ne inhibit hepatic drug uptake and that low-dose dopamine improves upt ake in IPRL.