Abstract
The concentrations of lidocaine and of its deethylated metabolite, MEGX, were measured in blood following the intravenous administration of 50 and 100 mg lidocaine hydrochloride, the oral administration of 100, 300, and 500 mg lidocaine hydrochloride monohydrate, and the oral administration of 300 mg lidocaine hydrochloride monohydrate every 8 h for seven doses, to three healthy volunteers. The range of values for the parameters defining the disposition kinetics of lidocaine were: terminal half-life, 50–231 min; total clearance, 13–17 ml/min/kg; initial dilution space, 0.13–2.5 liters/kg; and volume of distribution at steady state, 0.6–4.5 liters/kg. Lidocaine absorption from solution was rapid, but due to presystemic hepatic metabolism, the availability was low, the range of average values lying between 0.19 and 0.38. No dose or time dependency in lidocaine and monoethylglycinexylidide pharmacokinetics following the single dose studies of lidocaine were noted. Effective hepatic blood flow, based on total clearance and availability measurements, was estimated to be 18–27 ml/min/kg. The concentrations of MEGX were approximately one-third of those of lidocaine following intravenous lidocaine and were comparable following oral lidocaine, but as predicted, the dose normalized area under the MEGX concentration-time curve was constant and independent of the route of administration of lidocaine. In two subjects, the blood concentrations of lidocaine and MEGX following multiple doses of oral lidocaine were those predicted from the single dose studies. In the third subject, the degree of accumulation of lidocaine was greater than predicted. The reasons and mechanism for this difference between subjects on multiple dosing remains unclear.
Similar content being viewed by others
Abbreviations
- λ 1,λ 2 :
-
exponential coefficients associated with the first and second phase of the biexponential equation describing lidocaine disposition; min−1
- ANOVA:
-
analysis of variance
- AUC :
-
total area under the blood drug concentration-time curve; (mg/liter) × min
- CL :
-
total (blood) clearance of lidocaine; ml/min/kg
- EHBF:
-
effective hepatic blood flow; ml/min/kg
- F :
-
oral availability of lidocaine
- f m :
-
fraction of lidocaine converted to MEGX which appears in the general circulation. MEGX monoethylglycinexylidide
- t 1/2,1 t 1/2,2 :
-
half-life associated with the first and second phase, respectively, of lidocaine disposition; min
- t 1/2,abs :
-
absorption half-life of lidocaine; min
- t 1/2,MEGX :
-
elimination half-life of MEGX; min
- tlag:
-
time between administration and estimated start of lidocaine absorption; min
- V 1 :
-
initial dilution space of lidocaine; liters/kg
- V :
-
volume of distribution of lidocaine during the terminal phase; liters/kg
- V ss :
-
volume of distribution of lidocaine at steady state; liters/kg
- V MEGX :
-
volume of distribution of MEGX; liters/kg
References
M. Rowland, P. D. Thomson, A. Guichard, and K. L. Melmon. Disposition kinetics of lidocaine in normal subjects.Ann. N.Y. Acad. Sci. 179:383–398 (1971).
R. E. Stenson, R. T. Constantino, and D. C. Harrison. Interrelationships of hepatic blood flow, cardiac output and blood levels of lidocaine in man.Circulation. 43:205–211 (1971).
M. Rowland. Effect of some physiologic factors on bioavailability of oral dosage forms. In J. Swarbrick (ed.),Current Concepts in the Pharmaceutical Sciences: Dosage Form Design and Bioavailability. Lea and Febiger, Philadelphia, 1973, pp. 182–230.
R. N. Boyes, D. B. Scott, P. J. Jebson, M. J. Goodman, and D. G. Julian. Pharmacokinetics of lidocaine in man.Clin. Pharmacol. Ther. 12:105–116 (1971).
D. Lalka, C. V. Manion, A. Berlin, D. T. Baer, B. Dodd, and M. B. Meyer. Dose-dependent pharmacokinetics of lidocaine in volunteers.Clin. Pharmacol. Ther. 19:110 (1976).
E. Jahnchen, H. Bechtold, W. Kasper, F. Kersting, H. Just, J. Heykants, and T. Meinetz. Lorcainide. 1. Saturable presystemic elimination.Clin. Pharmacol. Ther. 26:187–195 (1979).
D. G. Shand and R. E. Rango. The disposition of propranolol.Pharmacology 7:159–168 (1972).
W. D. Mason and N. Winer. Pharmacokinetics of oxyprenolol in normal subjects.Clin. Pharmacol. Ther. 19:111–112 (1976).
B. Alexanderson. Pharmacokinetics of nortriptyline in man after single and multiple oral doses: the predictability of steady state plasma concentrations from single dose plasma-level data.Eur. J. Clin. Pharmacol:4:82–91 (1972).
G. H. Evans and D. G. Shand. Disposition of propranolol. V. Drug accumulation and steady-state concentrations during chronic oral administration in man.Clin. Pharmacol. Ther. 14:427–493 (1973).
L. E. Mather and G. T. Tucker. Meperidine and other basic drugs: general method of their determination in plasma.J. Pharm. Sci. 63:306–307 (1974).
H. Halkin, P. Meffin, K. Melmon, and M. Rowland. Influence of congestive heart failure on blood levels of lidocaine and its active monodeethylated metabolite.Clin. Pharmacol. Ther. 17:669–676 (1975).
M. Gibaldi and D. Perrier.Pharmacokinetics. Marcel Dekker, New York, 1975, pp. 48–57.
M. Gibaldi and D. Perrier.Pharmacokinetics. Dekker, New York, 1975, pp. 293–296.
A. H. Beckett, R. N. Boyes, and P. J. Appleton. The metabolism and excretion of lignocaine in man.J. Pharm. Pharmacol. 18(Suppl.):76–81 (1966).
J. C. K. Loo and S. Riegelman. New method for calculating the intrinsic absorption rate of drugs.J. Pharm. Sci. 57:918–923 (1968).
L. Turco, P. de Fillippi, V. Prinetti, and G. Segre. Kinetics of intestinal absorption of sulfamethazine in man.Clin. Pharmacol. Ther. 7:603–609 (1966).
E. L. Bradley. Measurement of hepatic blood flow in man.Surgery. 75:783–789 (1974).
D. G. Shand, D. M. Nickolls, and J. A. Oates. Plasma propranolol levels in adults with observations in four children.Clin. Pharmacol. Ther. 11:112–118 (1970).
R. Gomeni, G. Biachetti, R. Sega, and P. L. Morselli. Pharmacokinetics of propranolol in normal healthy volunteers.J. Pharmacokin. Biopharm. 5:183–192 (1977).
M. Rowland. Influence of route of administration on drug availability.J. Pharm. Sci. 61:70–74 (1972).
J. Casaer, S. Shaldon, L. Chiandassi, L. Guevara, and S. Sherlock. The use of indocyanin green in the measurement of hepatic blood flow.Clin. Sci. 21:43–57 (1961).
D. M. Kornhauser, A. J. J. Wood, R. E. Vestal, G. R. Wilkinson, R. A. Branch, and D. G. Shand. Biological determinants of propranolol disposition in man.Clin. Pharmacol. Ther. 23:165–174 (1978).
A. J. Atkinson and J. M. Strong. Effect of active drug metabolites on plasma level response correlations.J. Pharmacokin. Biopharm. 5:95–109 (1977).
K. S. Pang and M. Rowland. Hepatic clearance of drugs. III. Additional experimental evidence supporting the “well-stirred” model, using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused rat liverin situ preparation.J. Pharmacokin. Biopharm. 5:681–699 (1977).
G. Alvan, O. Borga, M. Lund, L. Palmer, and B. Siwers. First pass hydroxylation of nortriptyline: concentrations of parent drug and major metabolites in plasma.Eur. J. Clin. Pharmacol. 11:219–224 (1977).
J. G. Wagner, J. I. Northam, C. D. Alway, and O. S. Carpenter. Blood levels of drug in the equilibrium state after multiple dosing.Nature 207:1301–1302 (1965).
J. LeLorier, D. Grenon, Y. Latour, G. Caille, G. Dumont, A. Brosseau, and A. Solignac. Pharmacokinetics of lidocaine after prolonged intravenous infusions in uncomplicated myocardial infarction.Ann. Intern. Med. 87:700–702 (1977).
D. S. Frederick and R. B. Boersina. Lidocaine infusions: effect of duration and method of discontinuation on recurrence of arrhythmias and pharmacokinetics variables.Am. J. Hosp. Pharm. 36:778–781 (1979).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bennett, P.N., Aarons, L.J., Bending, M.R. et al. Pharmacokinetics of lidocaine and its deethylated metabolite: Dose and time dependency studies in man. Journal of Pharmacokinetics and Biopharmaceutics 10, 265–281 (1982). https://doi.org/10.1007/BF01059261
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01059261