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Pharmacokinetics of free-form levobupivacaine (LB) and free-form racemic bupivacaine (BU) using microdialysis sampling technique were conducted in this study. Three microdialysis probes were implanted in the jugular vein toward the right atrium, brain striatum and bile duct of male Sprague–Dawley rats for concurrently sampling free drug. Effects of P-glycoprotein (P-gp) on the brain distribution and hepatobiliary excretion of LB and BU were examined for the first time after cyclosporine (CsA) administration. LB and BU in samples were determined by HPLC. The blood pharmacokinetics of free LB and free BU were not significantly different. For brain pharmacokinetics, the CsA pretreatment raised significantly the area under curve (AUC) of BU (24.0 ± 5.9 vs. 14.6 ± 4.4 min μg/mL, p = 0.015). Brain regions concentrations of LB and BU were significantly higher than plasma concentrations of LB (p < 0.001) and BU (p < 0.001), respectively. The BU concentration of cerebral cortex was significant higher than that of striatum (6.06 ± 1.03 vs. 4.04 ± 0.90 μg/mL, p = 0.005) and hippocampus (6.06 ± 1.03 vs. 4.45 ± 1.07 μg/mL, p = 0.04), suggesting that BU might display an uneven brain distribution. For bile pharmacokinetics, LB and BU went through hepatobiliary excretion, and the AUC of BU was significantly higher than that of the LB group (6.6 ± 1.0 vs. 4.6 ± 0.6 min μg/mL, p = 0.005). In addition, the pretreatment of CsA significantly reduced the hepatobiliary excretion of BU in terms of AUC (4.4 ± 0.8 vs. 6.6 ± 1.0 min μg/mL, p = 0.003). Furthermore, the maximum concentration (Cmax) of BU diminished significantly as a result of the CsA pretreatment (0.10 ± 0.03 vs. 0.20 ± 0.05 μg/mL, p = 0.002). To sum up, enantioselective brain distribution and hepatobiliary excretion of free LB and free BU were observed, and P-gp may relate to the drug transport.