Abstract
Mass balance principles were used to describe the uptake and elution of lignocaine (lidocaine) and procainamide in the hindquarters of the sheep. Each of four sheep received a right atrial infusion of either lignocaine · HCl (2.7 mg/min) or procainamide · HCl (5.5mg/min) for 180 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken at 20-min intervals during the infusion and for 180 min after the infusion. Lignocaine and procainamide mean total body clearances were 2.9 L/min (SD 1.1) and 1.3 L/min (SD 0.2), respectively. An index of the uptake and elution of these drugs in the hindquarters was estimated from the net drug mass per unit hindquarter blood flow;indirect evidence suggested that hindquarter blood flow was constant. All the net mass/flow of procainamide that was taken into the hindquarters during the infusion also eluted after the infusion, demonstrating reversible distribution into the tissues. However, uptake of procainamide was still occurring when blood concentrations were constant, indicating that the concentrations of procainamide in the hindquarters were not in equilibrium with the inferior vena cava concentrations. Lignocaine did not reach constant blood concentrations during the infusion and showed no tendency to reach arteriovenous equilibration; an arteriovenous difference of 22%(SD5%) across the hindquarters was measured during the last 60 min of the infusion. By 180 min after the lignocaine infusions, 79% (SD 8%) of the lignocaine net mass/flow had not eluted from the hindquarters when arterial and venous lignocaine concentrations were not significantly different. This drug could remain uneluted due to metabolism and/or avid tissue binding, and presents difficulties in the interpretation of pharmacokinetic data whether based on arterial or venous blood sampling.
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References
L. E. Mather and W. B. Runciman. The physiological basis of pharmacokinetics: Concepts and tools. In H. O. Stoeckel (ed.),Quantitation, Modelling and Control in Anaesthesia, Georg Theime, Stuttgart, 1985, pp. 12–39.
R. N. Upton, L. E. Mather, W. B. Runciman, C. Nancarrow, and R. J. Carapetis. The use of mass balance principles to describe regional drug distribution and elimination.J. Pharmacokin. Biopharm. 16:13–29 (1988).
W. B. Runciman, A. H. Ilsley, L. E. Mather, R. J. Carapetis, and M. M. Rao. A sheep preparation for the study of the interaction between blood flow and drug disposition. I. Physiological Profile.Br. J. Anaesth. 56:1015–1028 (1984).
L. E. Mather, W. B. Runciman, R. J. Carapetis, A. H. Ilsley, and R. N. Upton. Hepatic and renal clearances of lidocaine in conscious and anesthetised sheep.Anesth. Analg. 65: 943–949 (1986).
W. B. Runciman, L. E. Mather, A. H. Ilsley, R. J. Carapetis, and C. F. McLean. A sheep preparation for the study of the interaction between blood flow and drug disposition. II. Experimental applications.Br. J. Anaesth. 56:1117–1129 (1984).
W. B. Runciman, R. N. Upton, A. H. Ilsley, R. J. Carapetis, T. M. Shepherd, C. Nancarrow, and L. E. Mather. Extra-visceral drug clearance.Clin. Exp. Pharmacol. Physiol. 10:677 (1983).
W. B. Runciman, L. E. Mather, A. H. Ilsley, R. J. Carapetis, and R. N. Upton. A sheep preparation for the study of the interaction between blood flow and drug disposition. III. Effects of general and spinal anaesthesia on regional blood flow and oxygen tensions.Br. J. Anaesth. 56:1247–1257 (1984).
M. L. Chen, M. G. Lee, and W. L. Chiou. Pharmacokinetics of drugs in blood III. Metabolism of procainamide and storage effects in blood samples.J. Pharm. Sci. 72: 572–574 (1983).
L. E. Mather and G. T. Tucker. Meperidine and other basic drugs: General method for their determination in plasma.J. Pharm. Sci. 63:306–307 (1974).
J. B. Bassingthwaighte. Plasma indicator dispersion in arteries of the human leg.Circ. Res. 14:332–346 (1966).
R. Barret, G. G. Graham, and T. A. Torda. The influence of sampling site upon the distribution phase kinetics of thiopentone.Anaesth. Intensive Care 12:5–9 (1984).
T. Terasaki, Y. Sugiyama, T. Iga, Y. Sawada, and M. Hanano. Theoretical consideration of drug distribution kinetics in a non eliminating organ: Comparison between a “homogenous (well stirred)” model and a “nonhomogenous (tube)” model.J. Pharmacokin. Biopharm. 13:265–287 (1985).
L. E. Gerlowski and R. K. Jain. Physiologically based pharmacokinetic modelling: Principles and applications.J. Pharm. Sci. 72:1103–1127 (1983).
G. Lam and W. L. Chiou. Determination of the steady state volume of distribution using arterial and venous plasma data from constant infusion studies with procainamide.J. Pharm. Pharmacol. 34:132–134 (1982).
L. E. Mather, W. B. Runciman, A. H. Ilsley, R. J. Carapetis and R. N. Upton. A sheep preparation for studying interactions between blood flow and drug disposition: V. Effects of general and spinal anaesthesia on blood flow and pethidine disposition.Br. J. Anaesth. 58:888–896 (1986).
W. B. Runciman, L. E. Mather, A. H. Ilsley, R. J. Carapetis, and R. N. Upton. A sheep preparation for studying interactions between blood flow and drug disposition: VI. Effects of general and spinal anaesthesia on blood flow and chlormethiazole disposition.Br. J. Anaesth. 58:1308–1316 (1986).
A. Junod. Uptake, release and metabolism of drugs in the lungs.Pharmacol. Ther. 2:511–521 (1976).
M. R. Juchau. Drug biotransformation in the placenta.Pharmacol. Ther. 8:501–524 (1980).
A. Pannatier, P. Jenner, B. Testa, and J. C. Etter. The skin as a drug metabolising organ.Drug Metab. Rev. 8:319–343 (1978).
J. C. Conelly and J. W. Bridges. The distribution and role of cytochrome P450 in extrahepatic organs.Prog. Drug Metab. 5:2–89 (1980).
W. Perl, H. Rackow, E. Salanitre, G. L. Wolf, and R. M. Epstein. Intertissue diffusion effect for inert fat soluble gases.J. Appl. Physiol. 20:621–627 (1965).
J. F. Hecker.The Sheep as an Experimental Animal, Academic Press, London, 1983, p. 50.
R. N. Upton, C. Nancarrow, L. E. Mather, W. B. Runciman, R. J. Carapetis, and C. F. McLean. Blood, muscle and fat lignocaine concentrations of the hindquarters of spinaily anaesthetised sheep.Clin. Exp. Pharmacol. Physiol. (in press, 1987).
W. L. Chiou and G. Lam. The significance of the arterial-venous plasma concentration difference in clearance studies.Int. J. Clin. Pharmacol. Ther. Toxicol. 20:197–203 (1982).
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This work was funded by a grant from National Health and Medical Research Council of Australia. RNU was funded by a National Health and Medical Research Council Biomedical Postgraduate Scholarship.
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Upton, R.N., Runciman, W.B., Mather, L.E. et al. The uptake and elution of lignocaine and procainamide in the hindquarters of the sheep described using mass balance principles. Journal of Pharmacokinetics and Biopharmaceutics 16, 31–40 (1988). https://doi.org/10.1007/BF01061861
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DOI: https://doi.org/10.1007/BF01061861