Lidocaine is a popular amide-type local anaesthetic agent. It is also used intravenously (i.v.) for the prevention and treatment of ventricular dysrhythmias. Lidocaine is eliminated mainly by metabolism and only small amounts are excreted unchanged in urine . Studies in vitro have shown that both cytochrome P-450 3A4 and 1A2 isoenzymes (CYP3A4 and CYP1A2) are important in the metabolism of lidocaine, their role being different at different lidocaine concentrations [2-4]. Recent studies have shown that fluvoxamine, a potent inhibitor of CYP1A2, considerably reduces the elimination of lidocaine [5,6].
Ciprofloxacin is a widely used broad-spectrum fluoroquinolone antibacterial agent . It is a moderately potent inhibitor of CYP1A2 and, for example, inhibits the metabolism of theophylline [8,9], caffeine  and another amide-type local anaesthetic, ropivacaine . Therefore, we wanted to study the effect of ciprofloxacin on the pharmacokinetics of lidocaine.
After obtaining institutional approval and informed written consent, six female and three male aged 21-29 yr and weighing 45-95 kg were studied. The study protocol was also accepted by the Finnish National Agency of Medicines and it was conducted according to the revised Declaration of Helsinki. Before entering the study the subjects were ascertained to be healthy by a clinical examination and monitoring a 12-lead electrocardiogram (ECG). None of the subjects was receiving continuous medication except for one female subject who was using contraceptive steroids. Based on previous studies , it was calculated that eight subjects would be required to demonstrate a 25% difference in area under the lidocaine plasma concentration-time curve (AUC) at a level of significance of P = 0.05 and power of 80%. Ten subjects were originally enrolled in the study, but one withdrew because of a common cold during the second study period.
A randomized, double-blinded, cross-over study design in two phases was used, at an interval of 4 weeks. The volunteers were randomized to receive either ciprofloxacin 500 mg (Ciproxin; Bayer, Germany) or placebo orally for 2.5 days at 08:00 and 20:00 h. On day 3, 1.5 mg kg−1 of lidocaine (Lidocard 20 mg mL−1; Orion, Finland) was administered as a constant infusion in 60 min. The lidocaine infusion was initiated 1 h after the administration of ciprofloxacin or placebo. The volunteers were allowed to have a light breakfast 2 h before administration of lidocaine and had a standard meal 3 and 6 h afterwards. Ingestion of alcohol, coffee, tea, cola and grapefruit juice was not allowed during the test day, nor was smoking permitted. During the infusion of lidocaine and for 2 h afterwards, the ECG of the subjects was monitored continuously. The infusions were given in a postanaesthesia care unit.
Blood sampling and determination of drug concentrations
Blood samples were drawn into ethylenediamine tetraacetic acid (EDTA) tubes just before the administration of lidocaine, at 30 and 60 min during the infusion, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 10 h after the cessation of the infusion. Plasma was separated within 30 min and stored at −40°C until analysis. Lidocaine, monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine) concentrations were analysed with gas chromatography using etidocaine as an internal standard [12,13]. The limit of quantitation of the method was 0.1 ng mL−1 for lidocaine and MEGX, and 0.05 ng mL−1 for 3-OH-lidocaine. The coefficient of variation (CV) was 5.0% at 7.9 ng mL−1 (n = 3) and 4.7% at 80.7 ng mL−1 (n = 4) for lidocaine. The corresponding values for MEGX were 2.1% at 8.4 ng mL−1 (n = 3) and 5.7% at 84.1 ng mL−1 (n = 7), respectively. The CV for 3-OH-lidocaine was 12.0% at 0.8 ng mL−1 (n = 4) and 5.4% at 7.8 ng mL−1. Plasma ciprofloxacin concentrations were measured from the samples drawn immediately before the administration of lidocaine (i.e. 1 h after ingestion of the last 500 mg dose of ciprofloxacin) and 1, 5 and 10 h after lidocaine infusion. Ciprofloxacin was quantified by liquid chromatography tandem mass spectrometry with electrospray ionization, using ofloxacin as an internal standard . The CV was 7.6% at 27.4 ng mL−1 (n = 3) and 3.7% at 794.7 ng mL−1 (n = 3).
The pharmacokinetics of lidocaine, MEXG and 3-OH-lidocaine were characterized by AUC, peak concentrations (Cmax) and elimination half-lives (t½). For MEGX and 3-OH-lidocaine, the concentration peak times (Tmax) were also identified. The elimination rate constant (kel) was determined by regression analysis of the terminal log-linear part of each lidocaine, MEGX and 3-OH-lidocaine concentration-time curve. The elimination half-life was calculated from t½ = ln 2/kel. The AUC was determined using the linear trapezoidal rule while successive concentration values were increasing, and the logarithmic trapezoidal rule when successive concentration values were decreasing after the peak concentration value. AUC was extrapolated to infinity by using the respective kel value. Values for plasma clearance (CL) and steady-state volume of distribution (Vss) of lidocaine were calculated using non-compartmental methods. We also calculated the ratio of AUC of MEGX and 3-OH-lidocaine to that of lidocaine (AUC ratio). The pharmacokinetic parameters were determined using the program MK model, version 5 (Biosoft, Cambridge, UK).
All data are expressed in the text and tables as mean values ± SD, except Tmax which is given as median (range). For clarity, mean concentrations ± SEM are given in Figure 1. Pharmacokinetic variables between the two phases were compared with t-test for paired data. The values for Tmax were compared with Wilcoxon signed ranks sum test. Differences were regarded statistically significant if P < 0.05. Data were analysed with the statistical program Systat for Windows, version 7.0 (SPSS, Chicago, IL, USA).
Compared to placebo, ciprofloxacin increased the mean Cmax and AUC of lidocaine by 12% (P < 0.05) and 26% (P < 0.01; Table 1, Fig. 1), respectively. The mean plasma CL of lidocaine was reduced by 22% (P < 0.01) and its t½ prolonged by 7% (P < 0.01) by ciprofloxacin (Table 1).
The Cmax of MEGX was decreased by 40% (P < 0.01) by ciprofloxacin but there was no significant change in the Tmax of MEGX (Fig. 1, Table 2). Ciprofloxacin decreased the AUC of MEGX by 21% (P < 0.01) and the t½ was prolonged by 34% (P < 0.05; Table 2).
The ratio of the AUC of MEGX to that of lidocaine was decreased by 40% (P < 0.001) by ciprofloxacin.
Ciprofloxacin decreased the Cmax of 3-OH-lidocaine by 23% (P < 0.05) and its AUC by 14% (P < 0.01; Fig. 1, Table 3). The Tmax and t½ of 3-OH-lidocaine were not significantly affected. However, the ratio of the AUC of 3-OH-lidocaine to that of lidocaine was decreased by 35% (P < 0.001) by ciprofloxacin.
The mean ciprofloxacin plasma concentration was 655 ng mL−1 before the administration of lidocaine and 288 ng mL−1 10 h after the lidocaine infusion (Fig. 1).
Apart from slight nausea in one subject during the ciprofloxacin phase, there were no side-effects during the study.
The CYP1A2 inhibitor ciprofloxacin affected the elimination of lidocaine by reducing moderately its plasma CL and increasing its Cmax and AUC. Ciprofloxacin also reduced the Cmax and AUC of the metabolites MEGX and 3-OH-lidocaine.
Lidocaine is eliminated mainly by metabolism . Lidocaine is de-ethylated to MEGX and further to glycinexylidide  and it is also metabolized via hydroxylation to 3-OH-lidocaine . In vitro both CYP3A4 and CYP1A2 isoenzymes can be important in the metabolism of lidocaine but their role is different at different lidocaine concentrations [2-4]. We have shown earlier that in vivo the inhibition of CYP3A4 either by erythromycin or itraconazole had practically no effect on the pharmacokinetics of i.v. lidocaine . Erythromycin and itraconazole reduced the CL of lidocaine insignificantly by 9% and 14%, respectively. However, fluvoxamine (100 mg daily), a potent but unselective inhibitor of CYP1A2, has greatly reduced the CL of lidocaine, on average by 41%  and 60% . Ciprofloxacin seems to be a less potent inhibitor of CYP1A2 than fluvoxamine . Therefore, the observed 22% decrease in lidocaine CL caused by ciprofloxacin (500 mg twice daily) in this study is in good agreement with the previous reports that ciprofloxacin is a moderately potent inhibitor of CYP1A2. The reduction of formation of both MEGX and 3-OH-lidocaine by ciprofloxacin demonstrates that CYP1A2 is important also in the formation of MEGX, which reaction was earlier thought to be mainly CYP3A4 mediated .
Continuous epidural infusion of 0.44-0.98 mg kg−1 h−1 of lidocaine for postoperative analgesia produced lidocaine plasma concentrations ranging from approximately 1 to 4 μg mL−1 . This is also the concentration range shown to be effective in the treatment of ventricular dysrhythmias . Lidocaine results in subjective toxic symptoms already at plasma concentrations from 3 to 5 μg mL−1 and objective signs appear at the level of 6 to 10 μg mL−1 . During the ciprofloxacin phase, the mean CL of lidocaine was reduced by 22% in this study. In four of the nine subjects, ciprofloxacin decreased the lidocaine CL by about 30-40%. As lidocaine has linear pharmacokinetics, this occurrence means that during a continuous epidural infusion of lidocaine its plasma concentrations could be increased up to 70% in these subjects.
The mean reduction of the CL of lidocaine by ciprofloxacin was smaller than previously observed for ropivacaine . Knowing the dissimilar extraction ratios of these two drugs, this is not surprising. Ropivacaine has an extraction ratio of 0.4 to 0.5 which makes its plasma CL more dependent on the enzymatic capacity of the liver than in the case of lidocaine . Lidocaine is a drug with high extraction ratio . Its CL is directly proportional to the liver blood flow and even major reduction in CYP1A2 activity does not challenge lidocaine CL as much as ropivacaine CL.
In conclusion, ciprofloxacin modestly reduces the elimination of lidocaine and may increase its systemic toxicity.
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