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Myocardial uptake of lignocaine: pharmacokinetics and pharmacodynamics in the isolated perfused heart of the rabbit
Author(s) -
Mazoit Jean Xavier,
Kantelip JeanPierre,
Orhant Edith Elisabeth,
Talmant JeanMichel
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14168.x
Subject(s) - pharmacodynamics , qrs complex , pharmacokinetics , compartment (ship) , perfusion , peripheral , lidocaine , lagomorpha , anesthesia , chemistry , steady state (chemistry) , first pass , medicine , pharmacology , oceanography , arithmetic , mathematics , geology
1 The uptake kinetics and pharmacodynamics of lignocaine were studied in the isolated perfused heart of the rabbit. 2 Six hearts were perfused with increasing concentrations of lignocaine in a modified Krebs‐Henseleit buffer. The effluent concentration together with the increase in QRS duration were measured during lignocaine infusion and during 20 min after cessation of lignocaine infusion. 3 Lignocaine disposition and elimination were best described by a two‐compartment open model. Terminal half‐life was 11.0 ± 2.9 min. The unidirectional transfer was slower from central to peripheral compartment than from peripheral to central compartment (T 1/2,12 = 42.6 ± 10.5 min whereas T 1/2,21 = 10.7 ± 2.8 min). The myocardium/perfusate concentration‐ratio was 4.7 ± 0.4. 4 The pharmacodynamic effect was best described in the central compartment by using the Hill equation. Calculated maximum QRS duration (E max ) was 77 ± 8 ms. E max was also directly measured in four additional rabbits by infusing ten times the dose of lignocaine used in the main experiment: the value of E max measured in these conditions was 92.5 ± 9.6 ms, i.e. a QRS widening of 150%. The steady‐state perfusate concentration producing half the effect (C 50 ) was 15.7 ± 7.6 μg ml −1 . 6 In conclusion, the specific lignocaine binding leading to increase in QRS duration appeared to be more closely related to the vascular stream than non specific binding leading to a deeper accumulation process.