Lidocaine is a popular amide-type local anesthetic that is also widely used for ventricular arrhythmias. It is eliminated mainly by hepatic metabolism and only traces are excreted unchanged in urine (1).
Studies in vitro have shown that both cytochrome P450 3A4 and 1A2 isoenzymes (CYP3A4 and CYP1A2) are important in the metabolism of lidocaine; their roles are different at different lidocaine concentrations (2–4). Erythromycin and itraconazole, both strong inhibitors of CYP3A4, have only a minor effect on the pharmacokinetics of IV lidocaine in humans (5,6). It was shown recently that the CYP1A2 inhibitor fluvoxamine decreases lidocaine clearance significantly (7). We have previously shown that the concomitant inhibition of CYP1A2 and CYP3A4 vigorously delays the elimination of another amide-type local anesthetic, ropivacaine (8). If the concomitant inhibition of CYP1A2 and CYP3A4 affected the pharmacokinetics of lidocaine to the same extent as it affects the pharmacokinetics of ropivacaine, it could considerably increase the toxicity of lidocaine. We therefore found it important to study the interaction of IV lidocaine with concomitantly administered fluvoxamine and erythromycin. Our hypothesis was that the administration of the CYP3A4 inhibitor erythromycin would further decrease the elimination of lidocaine when administered simultaneously with the CYP1A2 inhibitor fluvoxamine.
The study protocol was approved by the Ethics Committee of the Department of Surgery, Helsinki University Central Hospital, Helsinki, and by the Finnish National Agency of Medicines and was conducted according to the revised Declaration of Helsinki. Six female and 3 male volunteers, aged 19–27 yr and weighing 58–90 kg, participated in the study after giving their written informed consent. The subjects were ascertained to be healthy by a clinical examination and monitoring a 12-lead electrocardiogram (ECG) before entering the study. None of the subjects was receiving continuous medication except for one female subject who was using contraceptive steroids. Based on previous studies (1), it was calculated that eight subjects would be required to demonstrate a 25% difference in area under the lidocaine plasma concentration-time curve at a level of significance of P = 0.05 and power of 80%.
A randomized, double-blind, crossover study design in three phases was used, at an interval of two weeks between the phases. The subjects were given 100 mg fluvoxamine (Fevarin, Solvay Duphar, Holland) once a day and placebo thrice a day or 100 mg fluvoxamine once a day and 500 mg erythromycin (Ery-Max, Astra, Sweden) thrice a day or corresponding placebos. Erythromycin was given for 6 days and fluvoxamine for 5 days before lidocaine. On day 6, the dose of 1.5 mg/kg of IV lidocaine (Lidokainklorid 4 mg/mL, Kabi-Pharmacia, Sweden) was given over 60 min. Specifically, lidocaine infusion was started between 08.00 am and 08.30 am, 1 h after the administration of 500 mg erythromycin (or placebo) or 9 h after the last 100-mg dose of fluvoxamine (or placebo). The volunteers were allowed to have a light breakfast 1 h before administration of lidocaine and had standard meals 4 h and 7 h afterwards. Ingestion of alcohol, coffee, tea, cola, or grapefruit juice was not allowed during the test day, and smoking was not 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 postanesthesia care unit.
All samples were taken from a plastic cannula on the contralateral arm to that used for the administration of lidocaine. The cannula was kept patent with an obturator. Blood samples were drawn into EDTA tubes just before the administration of lidocaine and at 30 min and 60 min during the 60-min infusion. After the infusion, blood was sampled at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 10 h afterwards. Plasma was separated within 30 min and stored at −40°C until analysis. Concentrations of lidocaine and one of the major metabolites, monoethylglycinexylidide (MEGX), were analyzed with gas chromatography using etidocaine as an internal standard (9,10). The limit of quantitation was 2 ng/mL for both lidocaine and MEGX. The coefficient of variation was 5.3% at mean 10.5 ng/mL (n = 7) and 2.9% at mean 98.5 (n = 7) for lidocaine. The corresponding values for MEGX were 2.5% at mean 9.7 ng/mL (n = 7) and 4.0% at mean 98.9 ng/mL (n = 7), respectively. For the control of compliance, plasma fluvoxamine and erythromycin concentrations were measured from the samples drawn immediately before the administration of lidocaine. Concentrations of erythromycin were measured with high performance liquid chromatography (HPLC) using roxithromycin as an internal standard (11). The limit of quantitation was 0.2 mg/L and the coefficient of variation was 3% at mean 4.97 mg/L (n = 9). Fluvoxamine was quantified using haloperidol as an internal standard (12). The limit of quantitation was 10.0 ng/mL and the coefficient of variation was 4.5% at mean 85.7 ng/mL (n = 7) and 9.2% at mean 16.9 ng/mL (n = 7).
The pharmacokinetics of lidocaine and MEGX were characterized by areas under the drug plasma concentration-time curves (AUC), peak concentrations (Cmax), and elimination half-lives (t½). For MEGX, the concentration peak time (Tmax) was also identified. The elimination rate constant (kel) was determined by regression analysis of the log-linear part of each lidocaine and MEGX concentration-time curve. The elimination t½ was calculated as t½ = ln2/kel. The areas under the lidocaine concentration-time curves were calculated using the linear trapezoidal rule while successive concentration values were increasing and by the logarithmic trapezoidal rule when successive concentration values were decreasing after the Cmax value. AUC was extrapolated to infinity by using the respective kel value. Values for plasma clearance (CL) and steady-state volume of distribution of lidocaine were calculated using noncompartmental methods (13). We also calculated the ratio of AUC of MEGX to that of lidocaine (AUC ratio).
All data are expressed as mean values ± SD except in illustrations where, for clarity, values are given as mean ± SEM. Analysis of variance was used; a posteriori testing was done with Tukey’s test. Linear regression was used to estimate whether the measured erythromycin and fluvoxamine concentrations could be used to predict the change in the AUC values of lidocaine. Differences were regarded statistically significant if P < 0.05. Data were analyzed with the statistical program Systat for Windows, version 7.0 (SPSS, Chicago, IL).
Fluvoxamine alone reduced the mean CL of lidocaine to 59% of the control (placebo) value (P < 0.01) and prolonged the t½ of lidocaine from 2.6 ± 0.4 h to 3.5 ± 0.7 h (P < 0.01; Table 1; Fig. 1). During the combination of fluvoxamine and erythromycin, lidocaine CL was 21% smaller than during fluvoxamine alone (P < 0.05) and 53% smaller than during placebo (P < 0.001). The t½ of lidocaine (4.3 h) was significantly longer during the combination phase than during placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). Lidocaine steady-state volume of distribution was not affected by fluvoxamine or the combination of erythromycin and fluvoxamine.
Fluvoxamine alone and the combination of erythromycin and fluvoxamine considerably reduced the Cmax and AUC of MEGX and the ratio of AUC of MEGX to that of lidocaine (Table 2). However, fluvoxamine alone decreased the AUC of MEGX even more (P < 0.05) than the combination of erythromycin and fluvoxamine. The t½ of MEGX was prolonged significantly both by fluvoxamine alone and by the combination.
The mean plasma fluvoxamine concentration before the administration of lidocaine infusion was 56 ± 22 ng/mL during fluvoxamine treatment and 51 ± 28 ng/mL during the combined treatment with erythromycin and fluvoxamine. The corresponding concentration of erythromycin was 1.6 ± 0.6 mg/L during the combined treatment with erythromycin and fluvoxamine. The multiple linear regression model that included fluvoxamine and erythromycin concentrations as independent variables was able to predict the observed change in the AUC of lidocaine (r = 0.471; P < 0.05) (Figure 2).
The CYP1A2 inhibitor, fluvoxamine, markedly affected the elimination kinetics of lidocaine by reducing the mean plasma CL by 41%. The CL was decreased even further when lidocaine was administered after concomitant fluvoxamine and the CYP3A4 inhibitor, erythromycin. The large reduction of lidocaine CL was associated with prolongation of t½ and significantly increased AUC.
In vitro, both CYP3A4 and CYP1A2 enzymes can be important in the metabolism of lidocaine but their role is different at different lidocaine concentrations (2–4). It has been shown that, in humans, the inhibition of CYP3A4 alone, either by erythromycin or itraconazole, has only a minor effect on lidocaine CL (5,6). Our present study and that of Orlando et al. (7), however, demonstrate that the inhibition of CYP1A2 alone has a major effect on lidocaine pharmacokinetics. Furthermore, in our present study the concomitant inhibition of CYP3A4 (by erythromycin) and CYP1A2 (by fluvoxamine) clearly enhanced the effect of fluvoxamine on the pharmacokinetics of lidocaine. Although in our previous study erythromycin alone caused a 9% nonsignificant decrease in lidocaine CL, in the present study the same dose of erythromycin decreased lidocaine CL by 21% once CYP1A2 was inhibited. This is in agreement with the effect of fluvoxamine and erythromycin on the pharmacokinetics of ropivacaine (8). In the condition of an uninhibited CYP1A2, this enzyme can compensate for the role of CYP3A4 in the metabolism of lidocaine and ropivacaine when the latter enzyme is inhibited by erythromycin or other CYP3A4 inhibitors.
Continuous epidural infusion of lidocaine in doses 0.44–0.98 mg · kg−1 · h−1 for postoperative analgesia produced lidocaine concentrations ranging from approximately 1 to 4 μg/mL (14). This is also the concentration range shown to be effective in the treatment of ventricular arrhythmias (15). Because fluvoxamine reduced the mean lidocaine CL by 41% and the combination of fluvoxamine with erythromycin by 53%, it can be calculated that lidocaine concentrations during continuous epidural infusion would be increased on the average by 70% and 110%, respectively. This occurrence means that both the interaction between lidocaine and fluvoxamine and the interaction between lidocaine and the combination of fluvoxamine with erythromycin can result in lidocaine-induced toxicity because subjective toxic symptoms are already apparent at plasma concentrations 3 to 5 μg/mL and objective signs appear at 6 to 10 μg/mL (16,17).
The effect of the concomitant inhibition of CYP3A4 and CYP1A2 on the pharmacokinetics of lidocaine was less than that on the pharmacokinetics of ropivacaine (8). The difference in the magnitude of the interaction is most likely a result of dissimilar extraction ratios. Ropivacaine has an extraction ratio of 0.4–0.5, which makes its plasma clearance much more dependent on the enzymatic capacity of the liver than in the case of lidocaine (8). Lidocaine has a high extraction ratio (16). Accordingly, its clearance is directly proportional to liver blood flow and even major reduction in CYP3A4 and 1A2 activities do not change lidocaine CL as much as ropivacaine CL.
Both fluvoxamine and concomitant erythromycin and fluvoxamine reduced the Cmax and AUC of MEGX and increased its t½. However, erythromycin (inhibition of CYP3A4) partially prevented the decrease in the AUC of MEGX caused by fluvoxamine (CYP1A2 inhibition). Inhibition of other, CYP3A4-mediated, metabolic pathways of lidocaine by erythromycin seem to explain this effect. Similarly, erythromycin partially reverses the effect of fluvoxamine on the formation of 3-OH-ropivacaine from ropivacaine in humans (8). MEGX has 33%–83% of the antiarrhythmic activity of lidocaine and it can also cause convulsions (18). However, when lidocaine is administered together with fluvoxamine alone, or with a combination of erythromycin and fluvoxamine, the plasma concentrations of MEGX are not larger than usual and it does not contribute to the toxicity of lidocaine.
Of the generally used drugs, fluvoxamine is the most potent as an inhibitor of CYP1A2 enzyme. However, some other widely used drugs, e.g., the broad-spectrum fluoroquinolone antibacterial drug ciprofloxacin, significantly inhibit CYP1A2 enzyme and can interact with its substrate drugs. In addition to erythromycin, several other commonly used drugs (e.g., other macrolide antibiotics, azole antifungals, and human immunodeficiency virus-protease inhibitors) are potent inhibitors of CYP3A4. Thus, it is not uncommon that patients are using drugs concomitantly that inhibit both CYP1A2 and CYP3A4 enzymes and then require lidocaine.
We conclude that the inhibition of CYP1A2 by fluvoxamine considerably reduces the elimination of lidocaine. Concomitant use of fluvoxamine and the CYP3A4 inhibitor erythromycin further increases lidocaine concentration by decreasing its CL. The clinical implication of this study is that clinicians should be aware of the potentially increased toxicity of lidocaine when used together with the inhibitors of CYP1A2 and particularly with the combination of drugs which inhibit both CYP1A2 and CYP3A4 enzymes. Because the volume of distribution of lidocaine remains unchanged, the interaction is likely to have significant consequences only during continuous administration of lidocaine.
We thank Jouko Laitila, Kerttu Mårtensson and Lisbeth Partanen for skillful determination of lidocaine, MEGX, erythromycin and fluvoxamine plasma concentrations.
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© 2005 International Anesthesia Research Society
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