Ropivacaine is a new, long-acting local anesthetic, closely related structurally to the group of amino amides in present clinical use, e.g., bupivacaine and mepivacaine. Whereas these are available as racemates, ropivacaine has been developed as the pure S-(-)-enantiomer and does not exist in a racemic mixture. Ropivacaine has pharmacokinetic and pharmacodynamic properties resembling those of bupivacaine when given as a single injection [1-4]. When used for epidural anesthesia, ropivacaine has been well tolerated [5-7] in doses up to 200 mg, 10-20 mL ropivacaine 5-10 mg/mL (0.5%-1%). Solutions of ropivacaine 5-10 mg/mL are likely to have wide clinical application compared to bupivacaine  due to their lower systemic potential for central nervous system and cardiovascular toxicity [9-11]. Continuous infusion of low-concentration ropivacaine, alone or in combination with opioids, will have potential in prevention of postoperative pain after major surgical procedures [12,13].
The aim of the present study was to evaluate the pharmacokinetics of ropivacaine in comparison with bupivacaine when administered as a continuous epidural infusion for 21 h.
Thirty-seven male volunteers (mean age 27 yr [range 20-42], mean body weight 80 kg [range 60-98], mean height 182 cm [range 170-190]) were included in the study and written, informed consent was obtained from each participant. They were judged healthy based on a routine medical/physical examination, laboratory screening (hematology, blood chemistry, coagulation, and liver function), and electrocardiogram (ECG). The volunteers were allocated randomly to five parallel treatment groups (n = 8 per active treatment, n = 5 in placebo group). No differences were seen in the demographics of the various groups. The double-blind study was approved by the Ethics Committee of Orebro Medical Center Hospital, Orebro, Sweden.
All subjects fasted from midnight before the day of trial. Prior to administration of the epidural block, Ringer's acetate solution, 300 mL, was given as an intravenous (IV) infusion. The subjects were monitored during the entire period by personnel from the intensive care unit and during the night they were awakened for two to three short periods for safety checks. The epidural puncture was performed between 10:00 and 11:00 AM, starting with skin infiltration using 2-4 mL mepivacaine 5 mg/mL. With the subject in the horizontal lateral position, the L2-3 interspace was identified using the midline approach by the loss of resistance technique with an 18-gauge needle. After a 20-gauge epidural catheter had been inserted, a test dose of 3 mL of the study drug (according to the randomization list) was injected at a rate of 1 mL/s. The remaining 7 mL of the solution was injected in incremental doses over approximately 2 min. The catheter was then used for continuous infusion of the drug solution. The subjects received 10 mL/h of the study drug ropivacaine 1, 2, or 3 mg/mL (0.1%, 0.2%, or 0.3%) for 21 h corresponding to infusion rates of 10, 20, or 30 mg/h, respectively, or 25 mg/h bupivacaine 2.5 mg/mL (0.25%). The total doses of ropivacaine administered were 220 mg, 440 mg, and 660 mg, respectively, and the total dose of bupivacaine was 550 mg.
Peripheral blood samples, 5 or 10 mL each, were taken from an antecubital vein in the arm not used for the IV infusion of electrolyte solutions at time 0, and 30, 60, and 90 min, and 2, 3, 4, 5, 6, 8, 10, 12, 19, 21 (end of infusion), 21.5, 22, 23, 24, and 25 h after the start of injection of the bolus dose. The blood samples were centrifuged and the plasma was immediately frozen and maintained at -20 degrees C until assayed. The assay of total concentrations of ropivacaine and bupivacaine base in plasma was performed by means of gas chromatography with a nitrogen-sensitive detector, with limits of determination of 10 ng/mL and with coefficients of variation of approximately 5% for both drugs at 0.3 micro gram/mL . The free plasma concentrations were determined by liquid chromatography after ultrafiltration of the samples taken 5 and 30 min and 6 and 12 h after the start of the epidural injection. Free concentrations were detected by UV light at 210 nm, with limits of determination of 3 ng/mL and coefficients of variation less than 10% for both ropivacaine and bupivacaine . alpha-1-Acid glycoprotein (AAG) plasma concentrations were measured using a radioimmunodiffusion technique (NOR-Partigen Registered Trademark acid alpha1-Glycoprotein commercially prepared kits; Behring, Marburg, Germany) in the blood sample taken just before drug administration and in the 25-h sample, with limits of determination of 2 micro mol/L and a coefficient of variation of 7% at 18 micro mol/L .
The individual plasma concentrations of ropivacaine and bupivacaine were characterized by the mean concentrations between 5 and 10 h (C5-10h), since the levels seemed to be constant in this time interval, by the plasma concentration at the end of infusion 21 h (C21h), the terminal half-life (t1/2), the total area under plasma concentration-time curve (AUC), the apparent clearance (CL), and the free fraction (fu). The t1/2 was calculated from the terminal slope by linear regression. The total AUC was calculated by the linear trapezoidal rule up to the last data point plus the residual area up to infinity calculated by integration. Apparent CL was calculated assuming 100% bioavailability after epidural administration using the Equation CL= dose/AUC. The dose is the total dose of ropivacaine or bupivacaine base given (bolus dose [3 mL + 7 mL] + total dose infused). Ropivacaine base 194 mg, 388 mg, and 583 mg or bupivacaine base 488 mg correspond to 220 mg, 440 mg, and 660 mg ropivacaine hydrochloride or 550 mg bupivacaine hydrochloride, respectively. The fu was calculated by fu = Cu/C, where Cu is the free concentration at each sampling time and C is the total concentration at this time.
A one-way analysis of variance model was used for the three infusion rates of ropivacaine, assuming normally distributed data with equal variances. Any differences in C5-10h, C21h, t1/2, AUC, CL, and fu between the infusion rates were tested. For variables where there was a significant difference (P < 0.05) between the infusion rates, a test of dose proportionality was performed. As a hypothesis, a linear regression model was used in order to test linearity. In addition, a test was made of whether the intercept was zero. For CL, t1/2, and fu, a comparison was made between ropivacaine (10, 20, and 30 mg/h as one ropivacaine group) and bupivacaine (25 mg/h) treatments. Within each treatment group, Wilcoxon signed-rank tests were used to test the differences in total plasma concentration between C5-10h and C21h as well as between the free concentrations Cu,10h and Cu,21h. All results are expressed as mean (SD).
The plasma concentrations of both local anesthetics increased continuously throughout the 21-h infusion but seemed to reach a plateau after approximately 5 h of infusion, remaining constant up to approximately 10 h after the start of infusion (C5-10h) Figure 1. The mean C5-10h values were calculated on the basis of mean individual plateau levels as 0.3, 0.6, and 0.9 mg/L, respectively, when ropivacaine was administered at 10, 20, and 30 mg/h (P < 0.0001) and were proportional to the different infusion rates, i.e., showing a linear increase with no intercept. After 25 mg/h bupivacaine the plateau was calculated as 0.7 mg/L Table 1.
During the subsequent infusion, after 10 h the total plasma concentrations of both ropivacaine and bupivacaine increased, with the maximum levels occurring when the infusion pump was turned off (C21h; Table 1). All treatment groups showed statistically significant (P < 0.02) increases in plasma levels from 5-10 h to 21 h. The C21h for ropivacaine was proportional to the total dose, i.e., showing a linear increase with no intercept with increasing infusion rate.
The total plasma concentrations of ropivacaine and bupivacaine were monitored for 4 h (approximately one half-life) after the end of infusion. A definite decline was seen for both drugs and the t1/2 of ropivacaine was calculated as approximately 3 h and was independent of the infusion rate, while the t1/2 for bupivacaine was approximately 5 h--a difference that was statistically significant (P < 0.003) Table 1.
The mean apparent plasma CL values of ropivacaine were independent of the infusion rate and were estimated to be approximately 430 mL/min and after the administration of bupivacaine to be 423 mL/min Table 1.
(Figure 1) shows a semilogarithmic plot of the mean free concentrations versus time, together with the total concentrations after the administration of ropivacaine 10, 20, and 30 mg/h and bupivacaine 25 mg/h for 21 h. The free concentrations also increased continuously during the infusion Table 1. The fu of ropivacaine was calculated as 6.1(2.8)% and was independent of the infusion rate, while the f (u) of bupivacaine was calculated as 4.8% Table 1. The difference between ropivacaine and bupivacaine was, however, not statistically significant.
The plasma concentrations of AAG were estimated in the samples taken before drug administration to be 18(4) micro mol/L (range 10-30) and remained unchanged during the treatment. In the samples taken 25 h after the start of administration the levels were estimated to be 18(4) micro mol/L (range 12-28).
No differences were seen in the laboratory screening of the subjects after the infusion of ropivacaine, bupivacaine, or placebo for 21 h. None of the reported adverse events seemed to be related to systemic plasma concentrations of ropivacaine or bupivacaine Table 2.
This study was designed to evaluate the pharmacokinetics of ropivacaine after continuous epidural infusion in healthy volunteers. Healthy subjects were chosen for inclusion instead of patients, since patients receiving continuous epidural infusions form a heterogenous group and considerable variations in the results between individuals therefore could be expected. For example, the level of AAG which extensively binds ropivacaine as well as bupivacaine may be increased compared to normal levels  by a preexisting illness or by surgery. An increase in AAG level after surgery may have marked effects on the distribution and clearance of the drugs [12,17,18]. Surgery may also influence the liver blood flow, thereby affecting the clearance of the drugs .
After epidural administration of local anesthetics, differences in the physiochemical properties of different drugs have implications for the rate of absorption into the general circulation. When continuous infusion is used, excessive systemic and/or local accumulation is a potential cause of toxicity [19,20]. Systemic accumulation occurs when more drug reaches the circulation than is eliminated. After epidural administration, elimination is absorption-dependent [7,21]. Systemic accumulation seems to be more marked with the short-acting lidocaine compared to more local accumulation with the long-acting bupivacaine [19,21], as a result of the biphasic absorption process from the epidural space due to, for example, the lipid solubility.
In the present study the epidural infusions were judged to have been administered correctly based on the pharmacodynamics (sensory and motor block), and these results have been reported separately . There was a tendency for sensory block (pinprick with ropivacaine) to be dose-dependent (i.e., the spread was 8 dermatomes when given as 10 mg/h and 12 dermatomes when given as 30 mg/h). The administration rate 10 mg/h produced light motor block, with the result that the subjects were able to be mobilized throughout the study. The motor block was moderate and only occasionally could some of the subjects be mobilized when the infusion rates were 20 and 30 mg/h. The cranial spread of analgesia with bupivacaine did not differ from that produced by the rates of 20 and 30 mg/h ropivacaine, while the caudal spread was more stable. Bupivacaine caused the greatest intensity of motor block, and the regression phase was significantly longer than with ropivacaine. The analyses of the blood samples show a continuous increase in the plasma levels of both ropivacaine and bupivacaine during the 21-h infusion, although they seemed to reach a plateau between 5 and 10 h of infusion. During the following 11 h of infusion the plasma concentrations (total and free) increased again and peaked at the end of infusion. Unfortunately, out of consideration for the subjects rest, no blood samples could be taken during the night. Increasing plasma concentrations of bupivacaine not reaching a steady state are reported in other studies, where bupivacaine has been given as a prolonged postoperative infusion [12,22,23] or as intermittent epidural injections [17,24]. The plasma levels of AAG were constant throughout this study as expected, since it involved healthy volunteers, and no changes in the fu were seen in the plasma concentration range obtained. There was also an increase in free concentration between 12 and 21 h of infusion, which was almost comparable in percentage with the increase in total concentrations. The highest individual plasma concentration, 1.7 mg/L ropivacaine, was determined at the end of the 21-h infusion with 20 mg/h. No signs of systemic toxicity were seen in this or any other subject.
The apparent plasma clearances of approximately 430 mL/min for both ropivacaine and bupivacaine are somewhat higher than those earlier reported after epidural single injections (approximately 300 mL/min) . However, the circadian variation implies that this is a mean clearance over the day, and the increasing plasma levels during the night indicate a decreasing clearance during the night or a change in the absorption from the epidural space. After IV administration, the clearance of ropivacaine is reported to be 500 mL/min  and for bupivacaine, 610 mL/min . Local anesthetics of the amide type, such as ropivacaine and bupivacaine, are mainly eliminated by liver metabolism . Total plasma clearance of both ropivacaine and bupivacaine, which are characterized as low bordering on intermediate-extraction compounds [7,27], is therefore dependent on the enzyme activity and the plasma binding of the drug, but less dependent on the liver blood flow.
The terminal phase t1/2 was calculated over the 4-h period of blood sampling after the end of infusion. A definite decline was seen for both drugs Figure 1, despite their being monitored for approximately one t1/2. The t1/2 was estimated to be approximately 3 h for ropivacaine, which should be compared with the t1/2 of 1.9 h after IV administration . The t1/2 of 5 h for bupivacaine is also longer than that reported after IV administration, 2.7 h . Although these half-lives are shorter than those earlier reported after epidural single injections , they are probably an indication of absorption-dependent elimination, i.e., the elimination from the body/systemic circulation is faster than the absorption into the circulation, which might be explained by local accumulation in the epidural fat due to the high lipid solubility of the drugs [19,21].
In conclusion the total plasma concentrations, as well as the free concentrations of both ropivacaine and bupivacaine, increased continuously during the 21 h infusion but seem to reach a plateau between 5 and 10 h. The increases in the basic pharmacokinetic variables of ropivacaine were proportional to the increasing infusion rate in the dose range studied, with a maximum individual total plasma concentration of 1.7 mg/L ropivacaine (20 mg/h).
The authors gratefully acknowledge the Department of Bioanalysis, Astra Pain Control AB, for the analyses of ropivacaine, bupivacaine, and alpha1-acid glycoprotein. They would also like to thank Dr. Gunnar Englund for the statistical analysis.
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