Anesth Analg 2004;99:1131-1135
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000131508.39939.86
ANESTHETIC PHARMACOLOGY
Propofol Does Not Inhibit Lidocaine Metabolism During Epidural Anesthesia
Shin Nakayama, MD*,
Masayuki Miyabe, MD*,
Yoshihiro Kakiuchi, PhD ,
Shinichi Inomata, MD*,
Yoshiko Osaka, MD*,
Taeko Fukuda, MD*,
Yukinao Kohda, PhD, and
Hidenori Toyooka, MD*
Departments of *Anesthesiology and
Pharmacy, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan
Address correspondence and reprint requests to Masayuki Miyabe, MD, Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan. Address e-mail to miyabe{at}md.tsukuba.ac.jp
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Abstract
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Propofol is sometimes used in combination with epidural anesthesia with lidocaine. In this study, we investigated the effect of propofol on the plasma concentration of lidocaine and its principal metabolites during epidural anesthesia with lidocaine. Thirty-two patients were randomly allocated to receive either propofol or sevoflurane anesthesia (n = 16 each). In the propofol group, anesthesia was maintained with a target concentration of propofol of 4 µg/mL. In the sevoflurane group, anesthesia was maintained with 1.5% sevoflurane. Lidocaine was administered epidurally in an initial dose of 5 mg/kg, followed by a continuous infusion at 2.5 mg · kg–1 · h–1. Free components of plasma lidocaine and its metabolites—monoethylglycinexylidide (MEGX) and glycinexylidide (GX)—were measured 30, 60, 120, and 180 min after the initiation of continuous epidural injection by using high-performance liquid chromatography. Free lidocaine, MEGX, and GX were separated from 2 mL of plasma by ultrafiltration filter units. Hemodynamic data were similar between groups. The plasma concentrations of free lidocaine were not significantly different between groups. The ratios of free MEGX to free lidocaine and free GX to free MEGX were not different between groups. In conclusion, propofol does not alter the metabolism of epidural lidocaine compared with sevoflurane.
IMPLICATIONS: The potential for a drug interaction between propofol and epidurally administered lidocaine was tested. Propofol does not alter the metabolism of lidocaine in a clinical setting compared with sevoflurane. This finding implies that propofol can be used safely for general anesthesia combined with continuous epidural anesthesia with lidocaine.
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Introduction
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Propofol (2,6-diisopropylphenol) is generally thought to be catalyzed mainly by cytochrome P450 (CYP) 3A4 (1), and lidocaine is metabolized by CYP 3A4 (2) and 1A2 (2,3). When two drugs are metabolized by the same CYP isoforms, one drug could inhibit the metabolism of the other (4,5). We reported that propofol inhibits lidocaine metabolism in human and rat liver microsomes (6). Propofol is often used in combination with epidural anesthesia with lidocaine. Suppression of lidocaine metabolism might cause lidocaine intoxication. Therefore, the aim of this study was to investigate the effect of propofol on the metabolism of lidocaine during epidural administration.
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Methods
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Thirty-two patients, ASA physical status I or II, undergoing thoracic surgery participated in this study. Our protocol was approved by the local ethics committee, and informed consent was obtained from all patients. The patients were alternately assigned to one of two groups: patients in the control group were anesthetized with sevoflurane, and patients in the propofol group were anesthetized with IV propofol. Exclusion criteria included renal failure, hepatic dysfunction, heart disease, and treatment with any known inhibitor or inducer of CYP 1A2 or 3A4. All patients were premedicated orally with 150 mg of nizatidine 90 min before the induction of anesthesia. Bupivacaine 0.25% 5–10 mL was injected before insertion of a 17-gauge Tuohy needle into the T3-4 or T5-6 interspace (Arrow Epidural Catheterization Kit with Flex Tip Plus® catheter; Arrow International, Inc., Reading, PA). A 19-gauge epidural catheter was inserted into the epidural space through the Tuohy needle. In the control group, anesthesia was induced with 4 mg/kg of thiamylal. Tracheal intubation was facilitated with vecuronium (0.2 mg/kg). Anesthesia was maintained with 33% oxygen, 67% nitrogen, and 1%–2% sevoflurane. In the propofol group, anesthesia was induced and maintained with a plasma target concentration of propofol of 4 µg/mL by using a target-controlled infusion device (Diprifusor®; Terumo, Inc., Tokyo, Japan). Supplemental doses of fentanyl were administered if needed. After the induction of anesthesia, the lungs of the patients were mechanically ventilated, and PaCO2 was maintained between 35 and 45 mm Hg. A radial artery was cannulated for continuous monitoring of arterial blood pressure and blood sampling.
In both groups, an initial bolus of 2% lidocaine (5 mg/kg) was administered through the epidural catheter over 60 s, followed by a continuous lidocaine infusion at 2.5 mg · kg–1 · h–1. Mean arterial blood pressure was maintained more than 80 mm Hg during the study period by the administration of acetated Ringer’s solution or IV ephedrine. Arterial blood samples were drawn after 30, 60, 120, or 180 min of infusion. The plasma was separated by centrifugation at 4°C and stored –20°C until analyzed.
Plasma total and free concentrations of lidocaine, monoethylglycinexylidide (MEGX), and glycinexylidide (GX) were determined simultaneously by using high-performance liquid chromatography with ultraviolet detection (7) by using a variable wavelength ultraviolet detector (Model UV-8020; Tosoh, Japan) set for 210 nm. The high-performance liquid chromatography column (TSKgel ODS-80TS; Tosoh, Japan) was equilibrated with a mobile phase consisting of acetonitrile, methanol, and 0.05 M phosphate buffer adjusted to pH 4.0 (10:30:60; vol/vol) at a flow rate of 0.6 mL/min. Lidocaine, MEGX, and GX concentrations were assessed from peak-height ratios in comparison to an internal standard. With this assay method, the extraction recoveries from plasma for lidocaine, MEGX, and GX were 98.0%, 90.1%, and 73.2% at 10 µg/mL, respectively. The maximum coefficient of variation value for within-run or between-run precision was 3.3%; detection limits for lidocaine, MEGX, and GX were 10 ng/mL with 250 µL of plasma sample. To obtain free lidocaine, MEGX, and GX, plasma water was separated from 2 mL of plasma by using ultrafiltration filter units with centrifugation at 37°C and 2500g for 30 min (8).
Data are expressed as mean ± SD. Patient characteristics were analyzed with an unpaired Student’s t-test. Differences between groups with respect to plasma total or free lidocaine and MEGX were analyzed by two-way analysis of variance for repeated measures. Pairwise comparison of mean values were then assessed by the Scheffé F test. Values of P < 0.05 were considered significant.
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Results
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One patient in the control group was excluded from the analysis because the epidural catheter was not placed properly. The clinical characteristics of the patients are shown in Table 1. There were no significant differences between groups in patient characteristics, dose of acetated Ringer’s solution, blood loss, and ephedrine dose. Hemodynamic data during the study period are shown in Table 2. No significant differences were found between groups, although systolic blood pressure in the propofol group tended to be lower.
In all patients, the mean plasma concentration of MEGX increased continuously during the lidocaine infusion, whereas the mean plasma concentration of lidocaine remained at a steady-state level (Table 3). The plasma concentrations of lidocaine and free lidocaine were not different between groups. The plasma concentrations of MEGX were smaller in the propofol group than in the sevoflurane group at all sampling times (Table 3). The plasma concentrations of free MEGX were smaller in the propofol group than in the sevoflurane group at 30 and 60 min (Table 3). However, the free MEGX/free lidocaine ratio and the free GX/free MEGX ratio were similar in both groups (Fig. 1). These results demonstrated that the metabolic rate of lidocaine and MEGX did not significantly differ between groups. No patient had toxic symptoms or delayed emergence from anesthesia.
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Figure 1. The ratio of plasma free MEGX (monoethylglycinexylidide) to free lidocaine (M/L) and the ratio of plasma free GX (glycinexylidide) to free MEGX (G/M) during continuous epidural infusion of lidocaine. In the control group, anesthesia was maintained with sevoflurane. In the propofol group, anesthesia was maintained with propofol. Values are mean ± SD. There was no statistically significant difference between groups.
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Discussion
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The results of this study showed no inhibitory effects of propofol on the metabolism of lidocaine in comparison with sevoflurane anesthesia. The principal metabolism pathway of lidocaine in human is oxidative N-deethylation to MEGX in the liver (9). MEGX is then further deethylated to GX, the second-stage end product. Therefore, the formation of MEGX correlates with liver metabolism of lidocaine, and we analyzed the ratio of free MEGX to free lidocaine as an index of lidocaine metabolism. We chose free lidocaine instead of total lidocaine because free lidocaine is metabolized in the liver.
There are several possible reasons for the lack of inhibitory effects observed in this study. One is that the dose of propofol might have been too small to inhibit lidocaine metabolism. In an in vitro study, Leung et al. (5) showed that the plasma concentration of propofol required to inhibit the metabolism of midazolam was much larger (178 µg/mL) than the clinical concentrations (4–6 µg/mL). In an in vivo rat study, the IV infusion dose of propofol to inhibit CYP 450 was much larger (60 mg · kg–1 · h–1) (10) than the clinical dose (4–6 mg · kg–1 · h–1). Although, in a human study, Hamaoka et al. (1) reported that the target concentration of propofol of 22.5 µmol/L (4 µg/mL) inhibited the clearance of midazolam, lidocaine may be different. One of our investigators reported that propofol inhibits lidocaine metabolism in human and rat liver microsomes (6). In this study, the concentration of propofol that produced 50% maximal inhibition of lidocaine metabolism was 5.0 µg/mL. However, in an in vivo study, it was shown that propofol tightly binds to erythrocytes and serum albumin (11), and it was also noted that many in vitro studies used concentrations 50 to 500 times the concentration expected to be encountered in the immediate cellular environment. Therefore, it is possible that the propofol concentrations used in in vitro studies to inhibit lidocaine metabolism are much larger than the clinical doses.
The other possibility is that metabolic enzymes for propofol and lidocaine in the liver are not completely continuous. Propofol is metabolized not only by CYP 3A4 (1), but also by CYP 2B6 (12). Lidocaine is also metabolized both by CYP 3A4 and CYP 1A2 (2). It is reported that CYP 1A2 is a major determinant of lidocaine metabolism (two thirds) in vivo (3). Some CYPs that metabolize lidocaine may not be affected by propofol; therefore, it is possible that metabolism of lidocaine is not suppressed by propofol in the liver. Actually, it has been shown that even the effective inhibitors of CYP3A4, such as erythromycin and itraconazole, do not affect the pharmacokinetics of IV lidocaine to a clinically significant degree (13).
The other possibility is that the metabolism of lidocaine does not occur exclusively in the liver. It has been reported that more than 30% of MEGX is produced by extrahepatic metabolism (14). Therefore, it is possible that, even if propofol suppresses the metabolism of lidocaine in the liver, the net metabolism of lidocaine is not suppressed.
The plasma concentration of total lidocaine was smaller in the propofol group than in the sevoflurane group at 30 minutes. Although the mean arterial blood pressure was not statistically different between the groups, it is possible that the transfer of lidocaine from the epidural space to blood was less in the propofol group, because the mean arterial blood pressure tended to be lower in that group. However, because we chose the free MEGX/free lidocaine ratio as an index of lidocaine metabolism, we avoided the factor of the transfer of lidocaine from the epidural space to blood.
Liver blood flow might affect lidocaine metabolism (15). Although we could not measure liver blood flow, if the liver blood flow were less in the propofol group, the metabolic rate of lidocaine (free MEGX/free lidocaine) should have been less. However, it was not different between groups. This means that the liver blood flow did not affect the result of this study. The volume of distribution also may affect the lidocaine and MEGX concentrations. However, again because we compared the free MEGX/free lidocaine ratio, this factor might have been offset.
We assigned patients anesthetized by sevoflurane to a control group because sevoflurane is metabolized mainly by CYP 2E1 and has little inhibitory effect on lidocaine metabolism (16). We chose the epidural route instead of the IV route for lidocaine administration to investigate the effect of propofol on lidocaine metabolism. The IV route would have been a better model because it allows the calculation of pharmacokinetic variables such as clearance and volume of distribution. However, we thought it was also important to investigate the pharmacokinetics of epidural lidocaine, because we often use lidocaine and propofol simultaneously during epidural anesthesia.
In conclusion, propofol does not affect lidocaine metabolism in comparison with sevoflurane anesthesia during epidural administration.
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References
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Accepted for publication April 21, 2004.
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Abstract
Introduction
