Abstract
Prilocaine is assumed to undergo significant elimination by extrahepatic organs and to differ in this respect from other commonly used local anaesthetics. In order to clarify whether the lung may play an important role as a site of elimination of prilocaine, the kinetic parameters were studied in isolated perfused rat lungs and were compared to those of isolated livers. Furthermore, the structurally related compounds bupivacaine and mepivacaine were also investigated in this system. Prilocaine was dispersed into a relatively large apparent distribution volume in perfused rat lung (139 ml versus 97 ml in controls). In single-pass perfused lungs the observed maximum of concentration was decreased by about 60% compared to controls. The mean residence time was prolonged by about 40%. These observations suggest that prilocaine is substantially retained by rat lung and that this effect occurs particularly during first-pass.
However, the ability of rat lung to degrade prilocaine was relatively low. The clearance values were about 0.3 ml/min equal to about 20% of the hepatic capacity calculated per g of tissue. Thus it must be assumed that prilocaine is only transiently retained by the lung and will gain systemic availability later on. In rat lungs the kinetics of prilocaine elimination were not substantially different from those of bupivacaine and mepivacaine (16 and 12%). These observations do not support the assumption that especially prilocaine undergoes extrahepatic elimination.
For low (2 μg/ml) and intermediate (10 μg/ml) drug concentrations isolated rat liver exhibited clearance values close to the perfusion flow rate. Accordingly, prilocaine was removed from the perfusion medium of isolated livers already during first-pass. At very high concentrations of 100 μg/ml, the clearance dropped to about half of the control values. Thus under these conditions approximately half of the dose escaped first-pass extraction which is probably caused by saturated metabolic clearance. Such an effect was not observed for bupivacaine and mepivacaine.
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References
Akerman B, Astrom A, Ross S, Telc A (1966) Studies on the absorption, distribution and metabolism of labelled prilocaine and lidocaine in some animal species. Acta Pharmacol Toxicol 24:389–403
Arthur GR (1987) Pharmacokinetics of local anesthetics. In: Strichartz GR (ed) Local anesthetics. Handbook of experimental pharmacology, vol. 81, Springer, Berlin Heidelberg New York, pp 165–186
Arthur GR, Scott DHT, Boyes RN, Scott DB (1979) Pharmacokinetic and clinical pharmacological studies with mepivacaine and prilocaine. Br J Anaesth 51:481–485
Bachmann B, Biscoping J, Sinnung E, Hempelmann G (1990) Protein binding of prilocaine in human plasma: influence of concentration, pH and temperature. Acta Anaesth Scand 34:311–314
Bargetzi MJ, Aoyama T, Gonzalez FJ, Meyer UA (1989) Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4. Clin Pharmacol Ther 46:521–527
Burm AGL (1989) Clinical pharmacokinetics of epidural and spinal anaesthesia. Clin Pharmacokin 16:283–311
Foth H, Kietzmann D, Geng WP, Ebke M, Michaelis HC, Schroder T, Hering JP (1991) Pulmonary uptake of prilocaine, mepivacaine and bupivacaine. Naunyn-Schmiedeberg's Arch Pharmacol 343:R 5
Gibaldi M, Koup JR (1981) Pharmacokinetic concepts. Drug binding, apparent volume of distribution and clearance. Eur J Clin Pharmacol 20:299–305
Gibaldi M, Perrier D (1982) In: Gibaldi M, Perrier D (eds) Pharmacokinetics, 2nd edn. Marcel Dekker, New York, pp 45–50
Hems R, Ross BD, Krebs HA (1966) Gluconeogenesis in the perfused rat liver. Biochem J 101:2203–2206
Michaelis HC, Geng WP, Foth H, Kahl GF (1990) Sensitive determination of bupivacaine in human plasma by high performance liquid chromatography. J Chromatogr 527:201–207
Miller LL, Bly CG, Watson ML, Bale WF (1951) The dominant role of liver in plasma protein synthesis. J Exp Med 94:431–453
Moore DC, Crawford RD, Scurlock JE (1980) Severe hypoxia and acidosis following local anaesthetic-induced convulsions. Anaesthesiology 52:259–260
Oda Y, Imaoka S, Nakahira Y, Asada A, Fujimori M, Fujita S, Funae Y (1989) Metabolism of lidocaine by purified rat liver microsomal cytochromc P-450 isozymes. Biochem Pharmacol 24:4439–4444
Roberts MS, Fraser S, Wagner A, McLeod J (1990) Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: I. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate. J Pharmacokin Biopharm 18:209–234
Roerig DL, Kotrly KL, Vucins EJ, Ahlfs SB, Dawson CA, Kampine JP (1987) First-pass uptake of fentanyl, meperidine, and morphine in the human lung. Anesthesiology 69:466–472
Roerig DL, Kotrly KJ, Dawson CA, Ahlfs SB, Gualtieri JF, Kampine JP (1989) First-pass uptake of verapamil, diazepam, and thiopental in the human lung. Anesth Analg 67:461–466
Ross BD (1972) Isolated perfused lung. In: Ross BD (ed) Perfusion techniques in biochemistry. A laboratory manual in the use of isolated perfused organs in biochemical experimentation. Clarendon Press, Oxford, pp 439–455
Rothstein P, Cole JS, Pitt BR (1987) Pulmonary extraction of [3H]bupivacaine: Modification by dose, propranolol and interaction with [14C]5-hydroxytryptamine. J Pharmacol Exp Ther 240:410–414
Scott DB (1986) Toxic effects of local anaesthetic agents on the central nervous system. Br J Anaesth 58:732–735
Tucker GT (1986) Pharmacokinetics of local anaesthetics. Br J Anaesth 58:717–731
Tucker GT, Boas RA (1971) Pharmacokinetic aspects of intravenous regional anesthesia. Anesthesiology 34:538–549
Tucker GT, Mather LE (1988) Properties, absorption and disposition of local anesthetic agents. In: Cousins MJ, Bridenbaugh PO (eds) Neural blockade in clinical anesthesia and management of pain, 2nd edn. Philadelphia, Lippincott, pp 47–110
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Part of the doctoral thesis of Markus Ebke, Medical Faculty of the University of Göttingen
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Geng, W.P., Ebke, M. & Foth, H. Prilocaine elimination by isolated perfused rat lung and liver. Naunyn-Schmiedeberg's Arch Pharmacol 351, 93–98 (1995). https://doi.org/10.1007/BF00169069
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DOI: https://doi.org/10.1007/BF00169069