The effect of oral omeprazole on the disposition of lignocaine

Abstract

SummaryThe efects of the gastric antisecretory drug, omeprazole. on the disposition of lignocaine were studied in 10 healthy male volunteers in a double-blind, randomised, placebo-controlled, two-period crossover trial. Omeprazole 40 mg or placebo was taken daily for one week before administration of lignocaine I mg.kg-' (3.7 pmol.kg-') given intravenously over 10 min. Venous concentrations of lignocaine and its metabolite monoethylglycinexylidine were measured in plasma with reversed phase liquid chromatography. The mean (95% CI) areas under the curve at infinity for lignocaine after pretreatment with omeprazole or placebo were 6.67 (4.9043.45) pmol.h.1-' and 6.14 (5.05-7.23) pmol.h.l-', respectively ( p = 0.44). The respective areas for monoethylglycinexylidine were 1.85 (1.25-2.45) pmol.h.l-' and 1.79 (1.44-2.14) pmol.h.1-' ( p = 0.78). Similarly, omeprazole had no signijcant effect on the half-lives of lignocaine or methylglycinexylidine. Key wordsAnaesthetic, local; lignocaine. Pharmacokinetics. Pharmacology; omeprazoleOmeprazole is an antisecretory drug which inhibits K + , H+-ATP-ase in the gastric parietal cell resulting in long lasting reduction of gastric acid secretion [ 11. This drug has been shown to be effective in reducing acidity and volume of gastric contents in various situations and could prove useful as prophylaxis against the acid pulmonary aspiration syndrome and against stress-induced gastric ulceration or haemorrhage in at-risk patients [24].The H, receptor antagonists, cimetidine and ranitidine, have been shown to reduce hepatic clearance of lignocaine and other amide local anaesthetics [5-7l, although in the case of ranitidine this has not been a consistent finding [8].Omeprazole, in common with the H, receptor antagonists, has inhibitory effects on the hepatic microsomal cytochrome P450 system and may reduce the clearance of certain co-administered drugs [9]. Lignocaine, a drug with a narrow therapeutic range, may be administered in high doses concurrently with gastric antisecretory drugs to obstetric and critical care patients for nerve block or as an anti-arrhythmic. This study was designed to investigate a possible pharmacokinetic interaction between lignocaine and omeprazole. MethodsTen healthy male volunteers took part in a double-blind, placebo-controlled, two-period crossover study. With Ethics Committee approval, omeprazole (40 mg) or placebo was taken by mouth each morning for the 7 days preceding the study day and 1 h before intravenous lignocaine infusion on the morning of the study day. After arrival in the study room, the subjects took the test medication with 200 ml water and rested in a chair for 1 h before the infusion of lignocaine began. At that point they lay supine for baseline ECG and arterial blood pressure measurements and remained thus during the infusion. A minimum of 15 days elapsed between the two crossover phases whose order was by random allocation.On the study day, lignocaine hydrochloride (1 mg.kg-', 3.7 pmol.kg-') was infused intravenously over

Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein

“…These in vitro data might explain the significant increase in plasma levels of omeprazole and lansoprazole during coadministration of clarithromycin. Although CYP3A4 has been shown to be involved in the metabolism of proton pump inhibitors, no clinically relevant drug interactions could be found with numerous other CYP3A4 substrates (Ching et al 1991;Soons et al 1992;Blohme et al 1993;Galbraith and Michnovicz 1993;Noble et al 1994;Tateishi et al 1995) Therefore, a CYP3A4-independent mechanism was proposed for the clarithromycin/proton pump inhibitor interaction (Gustavson et al 1995;Langtry and Wilde 1997). As clarithromycin has been shown to be effective in inhibiting P-glycoprotein function (Wakasugi et al 1998;Wang et al 2000), inhibition of this transporter might contribute to this interaction.…”

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

“…The inhibitors of CYP2C19 (omeprazole) and CYP2D6 (propafenone) have little if any effect on intravenous lignocaine (Noble et al 1994;Ujhelyi et al 1993). Interestingly, although CYP3A4 is responsible for the formation of monoethylglycinexylidide in vitro, our study group has previously shown that erythromycin and itraconazole, both strong inhibitors of CYP3A4, have practically no effect on the pharmacokinetics of intravenous lignocaine (Isohanni et al 1998).…”

Pharmacokinetics, Metabolism and Interactions of Acid Pump Inhibitors

“…Omeprazole 20 to 40mg did not influence the metabolism of cyclosporin.I'<'I estradiol,D56] lidocaine, [88] nifedipine l78] or quinidine,lI57] which all are known to be CYP3A4 substrates; confidence in predicting that no other CYP3A4 substrate would be influenced by omeprazole is, therefore, rather high. Neither the biotransformation of prednisone to prednisolone nor the subsequent disposition of prednisolone, which are both potential CYP3A4 substrates, were affected by omeprazole.…”