Journal of JPP 2002, 54: 1221–1227 # 2002 The Authors Received April 27, 2002 Accepted June 9, 2002 ISSN 0022-3573 Kinetic and dynamic studies of liposomal bupivacaine and bupivacaine solution after subcutaneous injection in rats Hsiu-Ying Yu, Shyh-Dar Li and Pin Sun Abstract The pharmacodynamics and pharmacokinetics of bupivacaine in solution and in liposome prepara- tions following subcutaneous administration were studied in rats. Multilamellar vesicles entrapping bupivacaine solution were prepared. The local anaesthetic effect was estimated by the tail-ick test in Wistar rats treated with 1 mg bupivacaine in 0.2-mL preparations. Plasma concentrations of bupivacaine were determined by high-performance liquid chromatography. The results showed that both bupivacaine solution and bupivacaine liposomes revealed local anaesthetic effects in the initial tail-ick test (15 min after injection). With bupivacaine liposomes, the duration of action was 5-fold (44728.9 vs 876.7 min), the maximum possible effect was 2-fold (1000 vs 47.613%), and the peak plasma concentration (C max ) was less than one-fth (0.120.04 vs 0.650.04 g mL - 1 ) that with bupivacaine solution. The sensory block effect of bupivacaine solution completely resolved at 90 min, while the plasma concentration of bupivacaine was still more than half the C max . Bupivacaine liposomes resulted in a low and relatively constant plasma level (approx. 0.1 g mL - 1 ) and a pronounced local anaesthetic effect throughout the experimental period ( " 7 h). In conclusion, bupivacaine liposomes elevated the intensity and prolonged the duration of the local anaesthetic effect of bupivacaine, and suppressed the systemic absorption rate of encapsulated bupivacaine. Introduction Bupivacaine, an amide-type local anaesthetic, is widely used for in®ltration and regional anaesthesia. However, its undesirable eŒects of central nervous system and cardiac toxicity can cause severe problems (Bloci & Covino 1981 ; Catterall & Mackie 1996). It appears to be more cardiotoxic than other local anaesthetic agents. Since these toxic eŒects are directly related to the concentration of the drug in systemic circulation, inhibition of systemic drug absorption can greatly decrease the risk of systemic toxicity. In general, a vasoconstrictor is added to the local anaesthetic preparations in order to delay systemic absorption. However, some of the vasoconstriction agents may be absorbed, occasionally to an extent su cient to cause untoward reactions (Bloci & Covino 1981). Liposomes have been used as drug carriers in an attempt to bene®t drug therapy. Liposomal bupivacaine showed less systemic toxicity than bupivacaine solution after intravenous infusion in rabbits (Boogaerts et al 1993a). There is a report describing the plasma concentration of bupivacaine after plexus administration of bupivacaine liposomes and bupivacaine solution to rabbits (Boogaerts et al 1993b), but their anaesthetic eŒects were not studied or compared. Subcutaneous injection is one of the common routes of administration for local anaesthetic agents. However, the plasma concentration of bupivacaine after subcutaneous injection of its solution and liposomal formulation has not been reported. Since diŒerent administration routes may result in diŒerent plasma concentration pro®les, those observed after intravenous (Boogaerts et al 1993a) and plexus administration (Boogaerts et al 1993b) may not be extrapolated to subcutaneous administration. There are several types of liposomes, for example multilamellar vesicles, large unilamellar vesicles and small unilamellar vesicles. Multilamellar vesicles were School of Pharmacy College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100, Taiwan, Republic of China Hsiu-Ying Yu, Shyh-Dar Li, Pin Sun Correspondence : Hsiu-Ying Yu, School of Pharmacy College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100, Taiwan, Republic of China. E-mail : ying!ha.mc.ntu.edu.tw Acknowledgements and funding: The authors are grateful to Professors Wei-Zen Sun and Wen-Yeong Hou, Department of Anesthesiology, for their valuable comments on the tail-ick test. Bupivacaine hydrochloride crystalline powder was a generous gift from Astra, Sweden, via Taipei Branch. This study was supported by grants (NSC86-2815-C-002-063-B and NSC87-2815-C-002-082-B) from the National Science Council, Republic of China. 1221