Effect of ciprofloxin on the pharmacokinetics of intravenous lidocaine.

BACKGROUND AND OBJECTIVE: Recent studies have suggested that cytochrome P-450 isoenzyme 1A2 has an important role in lidocaine biotransformation. We have studied the effect of a cytochrome P-450 1A2 inhibitor, ciprofloxacin, on the pharmacokinetics of lidocaine. METHODS: In a randomized, double-blinded, cross-over study, nine healthy volunteers ingested for 2.5 days 500 mg oral ciprofloxacin or placebo twice daily. On day 3, they received a single dose of 1.5 mg kg[-1] lidocaine intravenously over 60 min. Plasma concentrations of lidocaine, 3-hydroxylidocaine and monoethylglycinexylidide were determined for 11 h after the start of the lidocaine infusion. RESULTS: Ciprofloxacin increased the mean peak concentration and area under plasma concentration-time curve of lidocaine by 12% (range [-6] to+46%; P<0.05) and 26% (8--59%; P 0.01), respectively. The mean plasma clearance of lidocaine was decreased by ciprofloxacin by 22% (7--38%; P<0.01). Ciprofloxacin decreased the area under the plasma concentration-time curve of monoethylglycinexylidide by 21% (P<0.01) and that of 3-hydroxylidocaine by 14% (P< 0.01). CONCLUSION: The plasma decay of intravenously administered lidocaine is modestly delayed by concomitantly administered ciprofloxacin. Ciprofloxacin may increase the systemic toxicity of lidocaine.

Effect of erythromycin and itraconazole on the pharmacokinetics of oral lignocaine.

Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(0-infinity)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P<0.01) and AUC(0-infinity) by 60% (P<0.01). The clinical implication of this study is that erythromycin and itraconazole may significantly increase the plasma concentrations and toxicity of oral lignocaine. The extent of the interaction of lignocaine with these CYP3A4 inhibitors was, however, less than that of, e.g. midazolam or buspirone, and it did not correlate with the CYP3A4 inhibiting potency of erythromycin and itraconazole.

Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine.

OBJECTIVE: We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design. METHODS: The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg x kg(-1) was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography. RESULTS: The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC(0-11 h) by 45-60%. CONCLUSION: The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine.

The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil.

UNLABELLED: The azole antimycotic fluconazole inhibits cytochrome P450 enzymes. We studied the possible interaction of alfentanil with oral and i.v. fluconazole in a three-phase, double-blind, placebo-controlled, randomized, cross-over study at intervals of 4 wk. Nine healthy volunteers were given a single oral dose of either fluconazole 400 mg or placebo, followed within 60 min by either i.v. fluconazole 400 mg in saline or saline only. The dose of 20 micrograms/kg of alfentanil was given i.v. 1 h after the fluconazole/placebo. Venous plasma samples were collected, and pharmacodynamic measurements were performed for 10 h. Alfentanil clearance was decreased from 3.1 +/- 1.1 mL.min-1.kg-1 to 1.3 +/- 0.3 mL.min-1. kg-1 after i.v. fluconazole and to 1.4 +/- 0.4 mL.min-1. kg-1 after oral fluconazole (P < 0.001). The mean elimination half-life of alfentanil was almost doubled after both oral and i.v. fluconazole (P < 0.001). Fluconazole increased the subjective effects of alfentanil as quantified on visual analog scales (P < 0.01). Correspondingly, both i.v. and oral fluconazole also increased the alfentanil-induced respiratory depression by decreasing the respiratory rate by 10%-15% (P < 0.05). We conclude that metabolism of alfentanil is inhibited by oral and i.v. fluconazole and that caution should be exercised when alfentanil is given to patients receiving fluconazole. IMPLICATIONS: We studied the interaction of cytochrome P450 3A4 enzyme inhibitor fluconazole with alfentanil. Nine volunteers were given placebo or fluconazole 400 mg orally or i.v. Alfentanil 20 micrograms/kg was given i.v. 1 h after pretreatment. Fluconazole decreased the clearance of alfentanil by 55% and increased the alfentanil-induced subjective effects.