Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients.

Abstract

1 The pharmacokinetics of lignocaine following single oral and intravenous doses have )een investigated in six normal volunteers and in six patients receiving chronic antiepile tic drug therapy. 2 After intravenous administration, serum lignocaine levels declined biexponentially in all subjects. The serum clearance (mean + s.d.) was slightly higher in the patients (0.85 + 0.09 v 0.77 + 0.07 1/min) but the difference was not statistically significant. 3 Lignocaine bioavailability after oral administration was more than two-fold lower in the patients than in the normal subjects (0.15 +0.06 v 0.37 +0.09, P < 0.001). 4 It is suggested that the reduced bioavailability of lignocaine in the patients is a consequence of stimulation of hepatic first-pass metabolism by antiepileptic drugs.

Differential effects of valproic acid and enzyme‐inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients.

“…The marked reduction in plasma nimodipine concentrations observed in patients taking enzyme-inducing agents (carbamazepine, phenobarbitone or phenytoin) may be explained by induction of pre-systemic metabolism. A marked reduction in oral bioavailability owing to induction of first pass-metabolism in anticonvulsanttreated epileptic patients has been described previously for many high-clearance drugs, including metyrapone (Meikle et al, 1972), lignocaine (Perucca & Richens, 1979) and other dihydropyridine calcium channel blockers such as felodipine (Capewell et al, 1988). An alternative explanation for the reduction in nimodipine bioavailability in our patients could be a decreased gastrointestinal absorption, possibly mediated by a change in bile acid concentration (Klaassen, 1971).…”

“…Among the latter, carbamazepine, phenytoin, phenobarbitone and primidone are potent inducers of the hepatic microsomal drug metabolizing enzymes (Perucca et al, 1984) and cause by this mechanism a large number of clinically significant interactions (Perucca, 1982;Pisani et al, 1990), including a reduction in the oral availability of drugs which, like dihydropyridines, undergo substantial first-pass metabolism (Capewell etal., 1988;Perucca & Richens, 1979). Of the main drugs used in the long-term treatment of the major epilepsies, only valproic acid is devoid of enzyme-inducing properties (Perucca et al, 1984), but a risk of interaction still exists because of the capacity of this compound to act as an inhibitor of oxidative (Kapetanovic et al, 1981) and non-oxidative (Jawad et al, 1987) 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 and 36 h after drug administration.…”

A comparative study of antipyrine and lignocaine disposition in normal subjects and in patients treated with enzyme‐inducing drugs.

“…The apparent oral clearance of the drug was calculated as dose/area under the serum concentration curve, corrected for the difference in concentration between serum and red cells. Details of the pharmacokinetic analysis are reported elsewhere (Perucca & Richens, 1979b). The serum concentration of antipyrine was determined by gas-liquid chromatography according to Lindgren, Collste, Norlander & Sjoqvist (1974 After oral administration of the hydrochloride monohydrate salt, serum lignocaine levels rose to peak values within 15-60 min and declined thereafter with a monoexponential decay in each of the subjects studied.…”

“…The concentration of lignocaine was determined in duplicate serum samples by enzyme-immunoassay (EMITR) as modified by Perucca & Richens (1979b). The apparent oral clearance of the drug was calculated as dose/area under the serum concentration curve, corrected for the difference in concentration between serum and red cells.…”

“…Under these conditions, and provided absorption is complete and metabolism is first-order, any change in hepatic drug metabolizing capacity will result in proportional but opposite changes in the oral bioavailability of the drug (Wilkinson & Shand, 1975;Alvan, Piafsky, Lind & von Bahr, 1979;Sotaniemi et al, 1978;Perucca & Richens, 1979a,b;Pantuck, Hsiao, Conney, Garland, Kappas, Anderson & Alvares, 1976) which, in turn, can be used as an indirect index of enzyme-induction or inhibition. Although the theoretical aspects of these principles have been considered in detail (Wilkinson & Shand, 1975;Perrier & Gibaldi, 1974;Rowland, 1972) (Stenson, Constantino & Harrison, 1971), primarily due to metabolic biotransformation by an enzymatic system which involves the mixed function oxidase (Strong, Parker & Atkinson, 1973;Hollunger, 1960;Keenaghan & Boyes, 1972) and has been shown to be inducible in animals (Di Fazio & Brown, 1972) and in man (Perucca & Richens, 1979b;Heinonen, Takki & Jahro, 1979); ii) virtually complete absorption from the gastrointestinal tract (Keenaghan & Boyes, (Bending, Bennett, Rowland & Steiner, 1976;Perucca, 1979;Boyes et al, 1971); iv) its previous use as a model drug in experiments designed to evaluate the perfusion-limited pharmacokinetic model in animals (Rane, Wilkinson & Shand, 1977;Branch, Shand, Wilkinson & Nies, 1973;Benowitz, Forsyth, Melmon & Rowland, 1974) and in man (Perucca & Richens, 1979b). This study provides further evidence in support of the hypothesis that the reduction of the oral bioavailability of lignocaine in epileptic patients is due to induction of the first-pass metabolism of the latter drug (Perucca & Richens, 1979b).…”