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Pharmacokinetics of the Enantiomers of Mepivacaine After Intravenous Administration of the Racemate in Volunteers

Burm, Anton G. L. MSc, PhD; Cohen, Imca M. C. MD; van Kleef, Jack W. MD, PhD; Vletter, Arie A. BSc; Olieman, Wim; Groen, Kees MSc, PhD

Regional Anesthesia and Pain Management

The pharmacokinetics of R(-)-mepivacaine and S(+)-mepivacaine were investigated in 10 healthy volunteers. The volunteers received racemic mepivacaine, hydrochloride (dose 60 mg) via a 10-min intravenous infusion. Blood samples were collected at gradually increasing intervals until 8 h after the start of the infusion. Plasma concentrations of the enantiomers were determined with a stereoselective high-performance liquid chromatographic (HPLC) method. Unbound fractions of the enantiomers were determined using equilibrium dialysis. The unbound fraction of R(-)-mepivacaine (mean +/- SD: 35.6% +/- 4.5%) was larger (P < 0.0001) than that of S(+)-mepivacaine (25.1% +/- 4.6%). The total plasma clearance and steady-state volume of distribution of R(-)-mepivacaine, based on total plasma concentrations (total plasma clearance [CL] = 0.79 +/- 0.12 L/min; volume of distribution at steady state [Vss] = 103 +/- 14 L) as well as on unbound plasma concentrations (plasma clearance of unbound drug [CLu] = 2.24 +/- 0.30 L/min; volume of distribution of unbound drug at steady state [V (uss)] = 290 +/- 32 L), were larger (P < 0.0001) than those of S(+)-mepivacaine (CL = 0.35 +/- 0.06 L/min; Vss = 57 +/- 7 L; CLu = 1.43 +/- 0.24 L/min; Vuss = 232 +/- 30 L). The terminal half-life (t1/2,Z) and mean residence time (MRT) of R(-)-mepivacaine (t1/2,Z = 113 +/- 17 min; MRT = 131 +/- 15 min) were shorter than those of S(+)-mepivacaine (t1/2,Z = 123 +/- 20 min, P < 0.02; MRT = 165 +/- 24 min, P < 0.0001). This study demonstrated a marked difference in the pharmacokinetics of the enantiomers of mepivacaine. The stereoselectivity can be partially explained by a difference in the plasma protein binding of the enantiomers.

(Anesth Analg 1997;84:85-9)

(Burm, Cohen, van Kleef, Vletter, Olieman) Department of Anaesthesiology, University Hospital Leiden, Leiden, The Netherlands, and (Groen) Unit Biotransformation, Pharmaco- and Toxicokinetics, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.

Section Editor: Denise J. Wedel.

This work was presented at the 16th annual meeting of the European Academy of Anaesthesiology, September 8-11, 1994 in Hamburg, Germany.

Accepted for publication August 15, 1996.

Address correspondence and reprint requests to Anton G. L. Burm, MSc, PhD, Department of Anaesthesiology, University Hospital Leiden, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Mepivacaine contains a chiral carbon center and exists in two stereoisomeric configurations, the enantiomers R(-)-mepivacaine and S(+)-mepivacaine. In a chiral environment, such as the body, enantiomers may exhibit different pharmacological activity. Animal studies comparing R(-)- and S(+)-mepivacaine indicated significant differences in the duration of nerve block and toxicity, favoring S(+)-mepivacaine [1-3]. A recent study in sheep demonstrated a significant difference in the pharmacokinetics of the enantiomers [4].

Clinically, mepivacaine is used as the racemate, containing equal amounts of R(-)- and S(+)-mepivacaine, prohibiting the establishment of possible differences in the nerve block characteristics and toxicity of the individual enantiomers in humans. Plasma concentrations of the enantiomers after administration of racemic mepivacaine for combined psoas compartment/sciatic nerve block have been shown to differ twofold, reflecting a marked difference in the pharmacokinetics of the enantiomers in humans [5]. However, a detailed pharmacokinetic interpretation of the plasma concentrations measured after perineural administration is not possible, since these concentrations are the net result of systemic absorption and systemic disposition (distribution and elimination). Therefore, we further explored the enantioselectivity in the pharmacokinetics of mepivacaine. In this study, racemic mepivacaine was given intravenously to healthy volunteers to assess both the distribution and elimination characteristics. In addition, we examined the protein binding of the enantiomers.

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Methods

The study protocol was approved by the Committee on Medical Ethics of the University Hospital Leiden. Ten nonsmoking, healthy male volunteers, aged 20-35 yr, weight 75-93 kg, were recruited, and they participated in the study after giving informed consent. Their state of health was confirmed on the basis of their medical history, physical examination, and laboratory tests, which included electrocardiogram, blood pressure, pulse frequency, urine analysis, hematology, and serum biochemistry. None of the volunteers were taking medical or nonmedical drugs. They refrained from food and drink (except for water) from midnight prior to the experiment until 3 h after drug administration, when they received a light lunch.

Experiments were performed in one of the operating rooms of the University Hospital Leiden. Supine volunteers, monitored with continuous electrocardiogram and noninvasive arterial blood pressure until 1 h after drug infusion, had two antecubital intravenous catheters introduced, one for drug infusion and a contralateral one for blood sampling. Racemic 1% mepivacaine hydrochloride was diluted with saline to a 3-mg/mL solution in a 50-mL syringe. A sample of this solution was taken and stored at -20 degrees C for determination of the enantiomeric composition. After collection of a 30-mL blood sample, 20 mL of the diluted solution (dose 60 mg) was infused at a constant rate (6 mg/min) in 10 min. The infusion always took place between 8 and 11 AM. Blood samples for the determination of the plasma concentrations of the enantiomers were collected in heparinized syringes at 2, 5, 10, 15, 20, and 30 min after the start of the infusion, then at 15-min intervals until 120 min, at 30-min intervals until 240 min, and from then on at 1-h intervals until 8 h after the start of the infusion. Arterial blood pressure and heart rate were recorded before and 5, 10, 15, 30, 45, and 60 min and 8 h after the start of the infusion.

Blood samples were centrifuged, and the obtained plasma was stored at -20 degrees C. To determine the degree of plasma protein binding of the enantiomers, racemic mepivacaine was added to blank plasma to obtain a concentration of 400 ng/mL of each enantiomer. Subsequently, plasma was subject to equilibrium dialysis at 37 degrees C for 4 h, as described previously [6], using a Dianorm [R] dialysis system, equipped with Teflon [R] dialysis cells (Diachema, Munchen, Germany), and the dialysate collected. Concentrations of R(-)- and S(+)-mepivacaine in the administered solution, plasma, and dialysate were determined by enantioselective high-performance liquid chromatography [7]. Whereas these analyses are based on determination of the peak heights of the enantiomers relative to that of an added internal standard, the enantiomeric composition of the administered solution was further examined by comparing the peak areas of the individual enantiomers. The interday coefficients of variation of this method were <9.5% and <9.1% at plasma concentrations of 10.5-1053 ng/mL of R(-)-mepivacaine and S(+)-mepivacaine, respectively. The intraday coefficients of variation were 5.0% at plasma concentrations of 263 ng/mL for both enantiomers. The quantification limit, corresponding with a coefficient of variation of 15%, was 5 ng/mL for both enantiomers.

The area under the plasma drug concentration-time curves (AUC) and the first moment of these curves (AUMC) were determined using the linear trapezoidal rule when concentrations were increasing and the logarithmic trapezoidal rule when concentrations were decreasing, with addition of the areas from the last sampling point until infinity [8]. Terminal rate constants (lambdaZ) were determined by linear regression of the terminal part (from 180, 210, or 240 min on) of the logarithm of the plasma concentration versus time curve. Terminal half-lives (t1/2,Z), mean residence times (MRT), total plasma clearance (CL), volumes of distribution at steady state (Vss) and during the log-linear terminal phase (V) were calculated as: t1/2,Z = ln(2)/lambdaZ; MRT = AUMC/AUC - T/2; CL = dose/AUC; Vss = CL [center dot] MRT; and V = CL/ lambdaZ, where T is the duration of the infusion [8-10]. Plasma clearances of unbound drug and volumes of distribution of unbound drug at steady state and during the log-linear terminal phase were obtained by dividing the corresponding values based on total plasma concentrations by the unbound fractions, as determined in the blank sample.

Data are summarized as mean +/- SD. Pharmacokinetic data of R(-)-mepivacaine and S(+)-mepivacaine were compared using the paired t-test. Hemodynamic data were analyzed using repeated measures analysis of variance. P < 0.05 was considered statistically significant.

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Results

The intravenous infusion of racemic mepivacaine was well tolerated by the volunteers and did not result in signs or symptoms indicative of systemic toxicity. Hemodynamic data did not change over time.

Analyses of the administered solutions showed that they were truely racemic, i.e., they contained equal concentrations of both enantiomers. The largest plasma concentrations were generally measured at the end of the infusion (Figure 1). However, in two subjects, the highest concentrations were reached 5 min after termination of the infusion. Total plasma concentrations of R(-)-mepivacaine during and after the infusion were lower than those of S(+)-mepivacaine in all subjects. Total concentrations at the end of the infusion were R(-)-mepivacaine, 505 +/- 168 ng/mL, and S(+)-mepivacaine, 673 +/- 207 ng/mL (P < 0.0001). Unbound plasma concentrations of R(-)-mepivacaine during the infusion were generally higher than those of S(+)-mepivacaine. Unbound concentrations at the end of the infusion were R(-)-mepivacaine, 177 +/- 58 ng/mL, and S(+)-mepivacaine, 167 +/- 53 ng/mL (P < 0.01). After the infusion the unbound concentrations of R(-)-mepivacaine were always lower than those of S(+)-mepivacaine.

Figure 1

Figure 1

Pharmacokinetic and statistical data are presented in Table 1. Unbound fractions of R(-)-mepivacaine were nearly 50% higher than those of S(+)-mepivacaine. The total plasma clearance and volumes of distribution of R(-)-mepivacaine were roughly twofold larger than those of S(+)-mepivacaine. The differences in the corresponding parameters based on unbound plasma concentrations were smaller, but the values were still larger for R(-)-mepivacaine compared with S(+)-mepivacaine.

Table 1

Table 1

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Discussion

There is increasing evidence that enantiomers of local anesthetics differ in their pharmacological and toxicological activity [1-3,11-14]. As far as mepivacaine is concerned, in vitro studies indicate no difference in the local anesthetic activity of the enantiomers [1]. Animal studies also indicate little or no difference in in vivo potency, but reveal a longer duration of action of S(+)-mepivacaine [1-3], probably reflecting a slower systemic absorption of S(+)-mepivacaine compared with R(-)-mepivacaine, due to more pronounced vasoconstriction [1,15]. An intradermal study in humans also demonstrated a longer duration of action of S(+)-mepivacaine [16] but did not confirm the more pronounced vasoconstriction. Toxicity studies showed that lethal doses (LD50) of the enantiomers of mepivacaine are similar upon rapid intravenous injection in rats and mice but somewhat larger for S(+)-mepivacaine than for R(-)-mepivacaine upon slower intravenous injection in mice and intravenous infusion in rabbits [1,2]. The LD50 value upon subcutaneous injection is considerably larger for S(+)-mepivacaine than for R(-)-mepivacaine in mice but not in rats.

Since mepivacaine is clinically used as the racemate, it is impossible to discern effects of the individual enantiomers. However, using enantioselective assays, plasma concentrations of the individual enantiomers can be distinguished. As such, the present study demonstrated a marked stereoselectivity in the pharmacokinetics of the enantiomers, confirming earlier observations of Vree et al. [5], who studied plasma concentrations of R(-)- and S(+)-mepivacaine (by the authors erroneously assigned R-(+)- and S(-)-mepivacaine) after administration of the racemate for combined psoas compartment/sciatic nerve block. In the present study, racemic mepivacaine was administered intravenously to avoid possible differences in the absorption rates of the enantiomers that complicate the interpretation of the plasma concentrationtime profiles. Comparison of the results of the study by Vree et al. [5] and the present study shows that the total plasma clearance of S(+)-mepivacaine (0.951 +/- 0.164 L/min) and R(-)-mepivacaine (0.543 +/- 0.201 L/min) were 20% and 53% higher, respectively, in the former study. Furthermore, steady-state volumes of distribution of S(+)-mepivacaine (243 +/- 60 L) and R(-)-mepivacaine (155 +/- 27 L) were more than two-fold larger in the study of Vree et al. [5]. The differences between the two studies may in part be due to differences in the populations (healthy volunteers versus premedicated patients). In addition, volumes of distribution, calculated from the plasma concentrations after extravascular administration, also account for the amount of drug at the site of injection, so that these volumes are by definition larger than those associated with intravenous administration. An additional difference between the two studies relates to the blood sampling site. Whereas Vree et al. [5] collected arterial blood samples, we preferred venous sampling for ethical reasons. However, total plasma clearances and steady-state volumes of distribution are not likely to be highly dependent on the sampling site, unless there is significant clearance in the upper extremity, in which case the calculated clearance would actually be larger with venous sampling.

When comparing plasma concentrations and pharmacokinetics of enantiomers, it is important to account for differences in their degree of plasma protein binding, since pharmacological and toxicological effects are generally believed to be more closely related to unbound than to total plasma concentrations. The present study examined the binding in individual plasma samples that were spiked with racemic mepivacaine and showed that the percentage of unbound S(+)-mepivacaine (25.1%) is considerably smaller than that of R(-)-mepivacaine (35.6%). In contrast, Tucker et al. [17] studied the binding in pooled plasma samples that were spiked with pure enantiomers and reported unbound percentages of S(+)-mepivacaine (33.0%) and R(-)-mepivacaine (38.1%) that were almost the same. The discrepancy between the two studies is most likely due to the difference in the spiked concentrations, which were much higher (5 vs 0.8 micro g/mL) in the study of Tucker et al. [17]. This explanation is consistent with observations in sheep plasma that, whereas the unbound percentage of S(+)-mepivacaine (23%) is much lower than that of R(-)-mepivacaine (32%) at low (0.5 micro g /mL) concentrations, unbound percentages are identical (45%) at high (10 micro g/mL) concentrations [4].

Knowledge of the degree of protein binding allows a more detailed interpretation of pharmacokinetic data. For example, the steady-state volume of distribution, based on total plasma concentrations of R(-)-mepivacaine, was approximately 1.8 times larger than that of S(+)-mepivacaine, whereas the volume based on unbound concentrations was 1.25 times larger. This indicates that the enantiomers of mepivacaine differ not only in their degree of binding to plasma proteins, but also in their degree of tissue binding. Also, the clearance based on total plasma concentrations of R(-)-mepivacaine was 2.25 times larger than that of S(+)-mepivacaine, whereas the clearance based on unbound concentrations was 1.58 times larger. This suggests that intrinsic clearances of the enantiomers also differ.

In the present study, total plasma concentrations of R(-)-mepivacaine during and after the infusion were smaller than those of S(+)-mepivacaine in all subjects, whereas unbound concentrations of R(-)-mepivacaine during, but not after, the infusion were slightly larger than those of S(+)-mepivacaine. This may reflect stereoselective rapid uptake into (followed by slow release from) tissue between the site of infusion and the sampling site, i.e., in the lungs and/or the upper extremity. Since the present study is based on venous sampling, discrimination between these two tissues is not possible. However, significant lung uptake has been demonstrated after epidural administration in patients [18]. Furthermore, stereoselectivity in the lung uptake of mepivacaine has been observed in rabbits [1]. Lung uptake attenuates arterial blood concentrations compared with those in the pulmonary artery, thereby protecting to some extent the target organs for toxicity, in particular when drug input is rapid, such as upon accidental intravenous injection [19]. Therefore, the stereoselectivity of the lung uptake deserves further investigation.

A previous study of the enantiomers of bupivacaine showed that the clearance based on total plasma concentrations of R(+)-bupivacaine was 1.25 times higher than that of S(-)-bupivacaine, whereas the clearance based on unbound concentrations was 0.84 times lower [20]. Also, volumes of distribution at steady state and during the terminal phase, based on total plasma concentrations of R(+)-bupivacaine, were 1.56 and 1.70 times larger than those of S(-)-bupivacaine, whereas the volumes based on unbound concentrations did not differ. In this respect, bupivacaine differs from mepivacaine. This is probably related to the difference in the lipophilicity of the drugs. Being more lipophilic, bupivacaine is expected to dissolve to a greater extent in fat tissue. Consequently, dissolution in fat may account for a greater portion of the tissue-bound drug with bupivacaine than with mepivacaine. The dissolution in fat is likely to be less stereoselective than the binding to other tissue constituents containing stereoisomeric macromolecules. Thereby, extensive dissolution in fat may mask any differences in the binding of bupivacaine to other tissue constituents and explain the lack of stereoselectivity in the volumes of distribution based on unbound drug concentrations.

The clinical relevance of the present study is not clear. The rationale for studying the pharmacokinetics of local anesthetics lies in the assumption that there is a direct relationship between the plasma concentrations of these drugs and (the severity of) systemic toxicity. However, data on the plasma concentration-toxicity relationship of mepivacaine in humans are scarce. Moreover, with the exception of the studies by Vree et al. [5] and the present study, all reports considering plasma concentrations of mepivacaine in humans are based on measurements of mixed enantiomers. Data from animal studies [1-3] are also inconclusive in that these examined dose-toxicity relationships (LD50 values) without concomitant measurement of plasma concentrations. This complicates extrapolation to humans as the enantioselectivity in the pharmacokinetics may be species dependent. For example, whereas the present study demonstrated marked differences in the clearance and volumes of distribution of the enantiomers of mepivacaine, based on either total or unbound plasma concentrations, studies in sheep only revealed a significant difference in the steady-state volume of distribution, based on total plasma concentrations, other parameters being comparable for both enantiomers [4].

In conclusion, this study demonstrates that the pharmacokinetics of mepivacaine are highly enantioselective. The finding that, overall, both total and unbound plasma concentrations of S(+)-mepivacaine are considerably larger than those of R(-)-mepivacaine may appear to be a disadvantage of the former drug. However, it is possible that the lower plasma concentrations of R(-)-mepivacaine are offset by a greater intrinsic toxicity. To date, toxicity data of the enantiomers of mepivacaine in humans are lacking. Therefore, the practical implications of our findings remain to be established.

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