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Effect of xylazine and ketamine on the pharmacokinetics of alfentanil during halothane anaesthesia
British Journal of Anaesthesia 1994; 72: 345-347
Effect of xylazine and ketamine on the pharmacokinetics of alfentanil during halothane anaesthesia P. J. PASCOE, W. D . BLACK AND E. P. STEFFEY
SUMMARY
KEY WORDS Pharmacokinetics alfentanil.
Alfentanil is a rapidly acting opioid with a short duration of activity. These properties are determined by its lipid solubility, protein binding and amount ionized at physiological pH. Initially the effects of alfentanil are limited by redistribution but it is also metabolized rapidly in the liver [1]. Recent studies have shown that this metabolism is delayed by the alpha2 adrenergic agonist, dexmedetomidine [1], and that the pharmacokinetics of alfentanil are altered by another alpha2 adrenergic agonist, clonidine [2]. This study was undertaken to examine the effect of xylazine, an alpha2 adrenergic agonist, in combination with ketamine, on the pharmacokinetics of alfentanil in horses anaesthetized with halothane. METHODS AND RESULTS
The study was approved by our institutional Animal Care Committee. We studied two thoroughbred horses, aged 3-4 yr. They were assessed as healthy by physical examination. Each animal was anaesthetized on three occasions, with at least 1 week between treatments. The order of treatments was randomized. The first treatment consisted of mask induction with halothane followed by a bolus injection of
P. J. PASCOE, B.V.SC, E. P. STEFFEY, V.M.D., PH.D., Department of
Surgery, School of Veterinary Medicine, University of California, Davis, CA 95616-8745, U.S.A., W. D. BLACK, D.V.M., PH.D.,
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G2W1, Canada. Accepted for Publication: September 17, 1993.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 7, 2015
We measured plasma concentrations of alfentanil in two horses after three different randomly ordered treatments. Each horse received halothane in oxygen by mask followed by a bolus dose of alfentanil 60 fig kg~' i.v., halothane in oxygen by mask followed by an i.v. alfentanil infusion for 120 min and xylazine and ketamine followed by halothane and a bolus dose of alfentanil 60 fig kg'1 i.v. Halothane was maintained at 1.05-1.07% end-tidal concentration with a PaCo2 of 6-7.3 kPa. The plasma concentration-time curves were similar after bolus and infusion doses of alfentanil with halothane and could be fitted to a two-compartment open model. A plateau was noted in the plasma concentrationtime curve in the presence of xylazine-ketamine which could not be modelled adequately, but suggested a three-compartment open model with an additional input component. (Br. J. Anaesth. 1994; 72:345-347)
alfentanil 60 ug kg l; the second treatment was the same except that alfentanil was given by infusion to a constant plasma concentration for 2 h; the third treatment consisted of induction with xylazine 1.1 mg kg"1 and ketamine 2.2 mg kg"1 followed by maintenance with halothane and the horses then received a bolus dose of alfentanil 60 ug kg"1. The horses weighed 386 and 468 kg, 396 and 471 kg and 407 and 473 kg for the three treatments, respectively. In each situation, the horses were tied to a tilting table and rotated into left lateral recumbency after induction with ketamine or before mask induction with halothane. When the animal was anaesthetized, the trachea was intubated and anaesthesia maintained with a circle rebreathing system containing halothane in oxygen. End-tidal gas was obtained from a centrally located catheter in the tracheal end of the tracheal tube and halothane was measured using an infra-red absorption technique (Model LB2, Beckman Instruments, Fullerton, CA, U.S.A.), calibrated against at least three known standards. End-tidal halothane concentration was adjusted to 1.05-1.07%. Ventilation was controlled using IPPV with an airway pressure of 18-20 cm H2O. Two catheters were placed in the jugular vein at least 25 cm apart (one for i.v. lactated Ringer's solution 3 ml kg"1 h"1 and one for sampling venous blood for measurement of concentrations of alfentanil) and one in the saphenous vein for infusion of alfentanil. Another catheter was placed in the facial artery for measurement of systemic arterial pressure and collection of samples for measurement of blood gas tensions and pH. PaCOi was mean 6.65 (SD 0.45) kPa and PaOj 64.2 (12.4) kPa. Alfentanil was administered via the saphenous venous catheter. After instrumentation and stabilization (85 (16) min after intubation), alfentanil was administered, either as a bolus for 45 s or from a computer controlled infusion pump which was designed to achieve and maintain a plasma alfentanil concentration of 170 ng ml"1 using a bolus and an exponentially decreasing infusion rate, allowing for elimination and transfer of drug between compartments (BET type infusion). The infusion was maintained for 2 h. In the studies of a
BRITISH JOURNAL OF ANAESTHESIA
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Time (min)
bolus of alfentanil, blood samples were obtained at 1, 2, 3, 4, 5, 10, 20, 40, 60, 90, 120, 150, 180, 210, 240, 300 and 360 min after the end of injection. After commencing the infusion, samples were obtained at 2, 4, 6, 10, 20, 30, 60, 90 and 120 min after the beginning of the infusion and then at 1, 3, 5, 10, 20, 40, 60, 90, 120, 150, 180, 210, 240, 300 and 360 min after the end of the infusion. Horses were kept anaesthetized for 2 h after the bolus or the end of the infusion before being moved to a recovery stall and allowed to recover. Total anaesthetic times were 237, 341 and 227 min, and 193, 343 and 210 min for each horse for the alfentanil bolus, alfentanil infusion and xylazine—ketamine—alfentanil bolus treatments, respectively. The times for recovery and standing for each horse are indicated in figure 1. The venous samples were centrifuged and plasma removed and frozen. The samples were stored at — 70 °C until analysis. Plasma concentrations of alfentanil were measured using a radioimmunoassay technique. The intra-assay coefficient of variation was 6.3% and the limit of detection 0.08 ng ml"1. The data were plotted in a semi-log fashion and components of the curve selected from the linear portions of the curve using a curve stripping technique. The steady state plasma concentrations of alfentanil after infusion for the two horses from 10— 120 min were 179.3 (22.6) and 168.7 (9.5) ngml" 1 . The results of the decay pharmacokinetics are shown in figure 1. The data for the horses anaesthetized with halothane alone (bolus or infusion of alfentanil) fitted a two-compartment open model, whereas the data from the xylazine-ketamine treatment appeared to fit a three-compartment elimination, with an additional input compartment, although we were unable to produce a satisfactory model for this treatment. A plateau was observed at 100-200 min. The slopes on the final decay and terminal elimination half-lives for all three treatments were very similar (0.01202 min"1
and 57.7 min, 0.0096 min"1 and 68.6 min, 0.01024 min"1 and 67.7 min for the alfentanil bolus, alfentanil infusion and xylazine-ketamine-alfentanil bolus, respectively). The area under the alfentanil concentration-time curves for the two bolus experiments were similar (17151 and 16 216 ng ml"1 min"1 for the alfentanil bolus and xylazine-ketaminealfentanil bolus treatments, respectively). COMMENT
Comparison of the bolus and infusion of alfentanil shows that the initial decrease in plasma concentrations of alfentanil was more rapid after the bolus dose. This is expected because the drug was being redistributed throughout the body whereas a 2-h infusion "saturates" some of these areas for redistribution resulting in a slower initial decrease in plasma concentrations. However, the slope of the elimination phase did not differ between the two treatments despite the longer duration of anaesthesia with the infusion of alfentanil. The pharmacokinetics of alfentanil in the horse were reported in a previous study which showed that alfentanil pharmacokinetics were affected significantly by anaesthesia [3]. In that study, the horses were anaesthetized with xylazine-ketamine followed either by halothane or isofiurane. Blood samples were collected for only 90 min after administration of alfentanil and the resulting pharmacokinetics were within 2 SD of the values reported for the two horses in this study. We have extended the time of sampling and shown that the elimination of alfentanil plateaus at this time and its decay did not continue until approximately 200 min after administration of alfentanil. This occurred after recovery of the horses as they were kept anaesthetized for 120 min and were standing at 163 and 176 min after the bolus dose of alfentanil (fig. 1). In the previous study, the effects of xylazine and ketamine on alfentanil were dis-
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 7, 2015
FIG. 1. Plasma concentration—time curves for alfentanil after three different treatments. Time 0 is the end of the bolus or infusion of alfentanil. The lines at the bottom of each graph show the duration of anaesthesia (A), the duration of recovery to standing (R) and the period standing until the end of the study (S), for each horse (A = horse 1, O = horse 2). A: Alfentanil bolus 60ugkg~' i.v. during halothane anaesthesia. The curve is described by the equation: concentration at time t (C,) = 654"0-1458' + 136"° °1202'. B : Alfentanil infusion for 120 min during halothane anaesthesia. The curve is represented by the equation: C, = 81.4~°-2736' + 101.7-° °096'. c: Alfentanil bolus 60 ug kg"1 i.v. after xylazine—ketamine and halothane anaesthesia. A reasonable solution for this curve was not obtained.
ALTERED PHARMACOKINETICS OF ALFENTANIL IN HORSES
circulation from a site of sequestration, such as alteration or shift in tissue or protein binding or a change in vascular volume. As alpha2 agonists are known to have significant effects on sympathetic tone, it is postulated that there was initially an enlarged vascular volume (more rapid distribution) which then contracted as the effects of xylazine diminished. ACKNOWLEDGEMENTS This work was funded by the Equine Research Laboratory, University of California, Davis, with funds provided by the Oak Tree Racing Association and the State of California Satellite Wagering Fund. Jannsen Pharmaceutical kindly provided the alfentanil used in the study. The authors thank Jim Jacobs for the software used to drive the alfentanil infusion pump and Abbott Laboratories for the use of the computer and infusion pump.
REFERENCES 1. Kharasch ED, Hill FH, Eddy AC. Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism. Anesthesiology 1991; 75: 520-524. 2. Segal IS, Jarvis DJ, Duncan SR, White PF, Maze M. Clinical efficacy of oral-transdermal clonidine combinations during the perioperative period. Anesthesiology 1991; 74: 220-225. 3. Pascoe PJ, Black WD, Claxton JM, Sansom RE. The pharmacokinetics and locomotor activity of alfentanil in the horse. Journal of Veterinary Pharmacology and Therapeutics 1991; 14: 317-325. 4. White PF, Marietta MP, Pudwill CR, Way WL, Trevor AJ. Effects of halothane anesthesia on the biodisposition of ketamine in rats. Journal of Pharmacology and Experimental Therapeutics 1976; 196: 545-555. 5. Steffey EP, Pascoe PJ. Xylazine reduces the isoflurane MAC in horses. Veterinary Surgery 1991; 20: 158. 6. Salonen JS. Pharmacokinetics of medetomidine. Ada Veterinaria Scandmavica 1989; (Suppl. 85): 49-54.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 7, 2015
counted because of the time between administration of these drugs and administration of alfentanil (approximately 60 min). When inhalation agents are not given, a horse will stand up within 15-30 min of induction with xylazine-ketamine but it has been shown in other species that the elimination of ketamine, at least, is slowed by administration of halothane [4], and it has been shown that this dose of xylazine has an effect on the MAC of isoflurane in horses for about 4 h [5]. Although it is not possible to differentiate the effects of the two i.v. drugs in this study, evidence from other species suggests that xylazine is likely to have a modifying effect on the elimination of alfentanil. Dexmedetomidine was found to slow the hepatic metabolism of alfentanil but in the concentrations used it is unlikely that this effect is relevant clinically. That experiment showed that the threshold for inhibition of metabolism was approximately 0.2 \imol litre"1 or 47 ug ml"1 [1] and in a study in dogs receiving medetomidine 80 ug kg"1 i.v., the peak plasma concentration was about 35 ng ml"1 [6]. As clonidine has also been shown to alter the pharmacokinetics of alfentanil and there appears to be no effect on hepatic metabolism [1], the present experiment lends further evidence for an interaction between alfentanil and alpha2 adrenergic agonists. Our data indicate that metabolism was not affected, as the terminal elimination slopes were virtually identical when the concentration-time curve was past the plateau and the area under the curve was the same for both bolus treatments. Initially, alfentanil appeared to be undergoing greater distribution under the influence of xylazine-ketamine, as it reached smaller concentrations more rapidly. The plateau probably represents an input of the drug into the
347
Effect of xylazine and ketamine on the pharmacokinetics of alfentanil during halothane anaesthesia P. J. PASCOE, W. D . BLACK AND E. P. STEFFEY
SUMMARY
KEY WORDS Pharmacokinetics alfentanil.
Alfentanil is a rapidly acting opioid with a short duration of activity. These properties are determined by its lipid solubility, protein binding and amount ionized at physiological pH. Initially the effects of alfentanil are limited by redistribution but it is also metabolized rapidly in the liver [1]. Recent studies have shown that this metabolism is delayed by the alpha2 adrenergic agonist, dexmedetomidine [1], and that the pharmacokinetics of alfentanil are altered by another alpha2 adrenergic agonist, clonidine [2]. This study was undertaken to examine the effect of xylazine, an alpha2 adrenergic agonist, in combination with ketamine, on the pharmacokinetics of alfentanil in horses anaesthetized with halothane. METHODS AND RESULTS
The study was approved by our institutional Animal Care Committee. We studied two thoroughbred horses, aged 3-4 yr. They were assessed as healthy by physical examination. Each animal was anaesthetized on three occasions, with at least 1 week between treatments. The order of treatments was randomized. The first treatment consisted of mask induction with halothane followed by a bolus injection of
P. J. PASCOE, B.V.SC, E. P. STEFFEY, V.M.D., PH.D., Department of
Surgery, School of Veterinary Medicine, University of California, Davis, CA 95616-8745, U.S.A., W. D. BLACK, D.V.M., PH.D.,
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G2W1, Canada. Accepted for Publication: September 17, 1993.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 7, 2015
We measured plasma concentrations of alfentanil in two horses after three different randomly ordered treatments. Each horse received halothane in oxygen by mask followed by a bolus dose of alfentanil 60 fig kg~' i.v., halothane in oxygen by mask followed by an i.v. alfentanil infusion for 120 min and xylazine and ketamine followed by halothane and a bolus dose of alfentanil 60 fig kg'1 i.v. Halothane was maintained at 1.05-1.07% end-tidal concentration with a PaCo2 of 6-7.3 kPa. The plasma concentration-time curves were similar after bolus and infusion doses of alfentanil with halothane and could be fitted to a two-compartment open model. A plateau was noted in the plasma concentrationtime curve in the presence of xylazine-ketamine which could not be modelled adequately, but suggested a three-compartment open model with an additional input component. (Br. J. Anaesth. 1994; 72:345-347)
alfentanil 60 ug kg l; the second treatment was the same except that alfentanil was given by infusion to a constant plasma concentration for 2 h; the third treatment consisted of induction with xylazine 1.1 mg kg"1 and ketamine 2.2 mg kg"1 followed by maintenance with halothane and the horses then received a bolus dose of alfentanil 60 ug kg"1. The horses weighed 386 and 468 kg, 396 and 471 kg and 407 and 473 kg for the three treatments, respectively. In each situation, the horses were tied to a tilting table and rotated into left lateral recumbency after induction with ketamine or before mask induction with halothane. When the animal was anaesthetized, the trachea was intubated and anaesthesia maintained with a circle rebreathing system containing halothane in oxygen. End-tidal gas was obtained from a centrally located catheter in the tracheal end of the tracheal tube and halothane was measured using an infra-red absorption technique (Model LB2, Beckman Instruments, Fullerton, CA, U.S.A.), calibrated against at least three known standards. End-tidal halothane concentration was adjusted to 1.05-1.07%. Ventilation was controlled using IPPV with an airway pressure of 18-20 cm H2O. Two catheters were placed in the jugular vein at least 25 cm apart (one for i.v. lactated Ringer's solution 3 ml kg"1 h"1 and one for sampling venous blood for measurement of concentrations of alfentanil) and one in the saphenous vein for infusion of alfentanil. Another catheter was placed in the facial artery for measurement of systemic arterial pressure and collection of samples for measurement of blood gas tensions and pH. PaCOi was mean 6.65 (SD 0.45) kPa and PaOj 64.2 (12.4) kPa. Alfentanil was administered via the saphenous venous catheter. After instrumentation and stabilization (85 (16) min after intubation), alfentanil was administered, either as a bolus for 45 s or from a computer controlled infusion pump which was designed to achieve and maintain a plasma alfentanil concentration of 170 ng ml"1 using a bolus and an exponentially decreasing infusion rate, allowing for elimination and transfer of drug between compartments (BET type infusion). The infusion was maintained for 2 h. In the studies of a
BRITISH JOURNAL OF ANAESTHESIA
346 1000
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Horse 1 Horse 2
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1000i
100-
100-
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60 120 180 240 300 360
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I
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bolus of alfentanil, blood samples were obtained at 1, 2, 3, 4, 5, 10, 20, 40, 60, 90, 120, 150, 180, 210, 240, 300 and 360 min after the end of injection. After commencing the infusion, samples were obtained at 2, 4, 6, 10, 20, 30, 60, 90 and 120 min after the beginning of the infusion and then at 1, 3, 5, 10, 20, 40, 60, 90, 120, 150, 180, 210, 240, 300 and 360 min after the end of the infusion. Horses were kept anaesthetized for 2 h after the bolus or the end of the infusion before being moved to a recovery stall and allowed to recover. Total anaesthetic times were 237, 341 and 227 min, and 193, 343 and 210 min for each horse for the alfentanil bolus, alfentanil infusion and xylazine—ketamine—alfentanil bolus treatments, respectively. The times for recovery and standing for each horse are indicated in figure 1. The venous samples were centrifuged and plasma removed and frozen. The samples were stored at — 70 °C until analysis. Plasma concentrations of alfentanil were measured using a radioimmunoassay technique. The intra-assay coefficient of variation was 6.3% and the limit of detection 0.08 ng ml"1. The data were plotted in a semi-log fashion and components of the curve selected from the linear portions of the curve using a curve stripping technique. The steady state plasma concentrations of alfentanil after infusion for the two horses from 10— 120 min were 179.3 (22.6) and 168.7 (9.5) ngml" 1 . The results of the decay pharmacokinetics are shown in figure 1. The data for the horses anaesthetized with halothane alone (bolus or infusion of alfentanil) fitted a two-compartment open model, whereas the data from the xylazine-ketamine treatment appeared to fit a three-compartment elimination, with an additional input compartment, although we were unable to produce a satisfactory model for this treatment. A plateau was observed at 100-200 min. The slopes on the final decay and terminal elimination half-lives for all three treatments were very similar (0.01202 min"1
and 57.7 min, 0.0096 min"1 and 68.6 min, 0.01024 min"1 and 67.7 min for the alfentanil bolus, alfentanil infusion and xylazine-ketamine-alfentanil bolus, respectively). The area under the alfentanil concentration-time curves for the two bolus experiments were similar (17151 and 16 216 ng ml"1 min"1 for the alfentanil bolus and xylazine-ketaminealfentanil bolus treatments, respectively). COMMENT
Comparison of the bolus and infusion of alfentanil shows that the initial decrease in plasma concentrations of alfentanil was more rapid after the bolus dose. This is expected because the drug was being redistributed throughout the body whereas a 2-h infusion "saturates" some of these areas for redistribution resulting in a slower initial decrease in plasma concentrations. However, the slope of the elimination phase did not differ between the two treatments despite the longer duration of anaesthesia with the infusion of alfentanil. The pharmacokinetics of alfentanil in the horse were reported in a previous study which showed that alfentanil pharmacokinetics were affected significantly by anaesthesia [3]. In that study, the horses were anaesthetized with xylazine-ketamine followed either by halothane or isofiurane. Blood samples were collected for only 90 min after administration of alfentanil and the resulting pharmacokinetics were within 2 SD of the values reported for the two horses in this study. We have extended the time of sampling and shown that the elimination of alfentanil plateaus at this time and its decay did not continue until approximately 200 min after administration of alfentanil. This occurred after recovery of the horses as they were kept anaesthetized for 120 min and were standing at 163 and 176 min after the bolus dose of alfentanil (fig. 1). In the previous study, the effects of xylazine and ketamine on alfentanil were dis-
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 7, 2015
FIG. 1. Plasma concentration—time curves for alfentanil after three different treatments. Time 0 is the end of the bolus or infusion of alfentanil. The lines at the bottom of each graph show the duration of anaesthesia (A), the duration of recovery to standing (R) and the period standing until the end of the study (S), for each horse (A = horse 1, O = horse 2). A: Alfentanil bolus 60ugkg~' i.v. during halothane anaesthesia. The curve is described by the equation: concentration at time t (C,) = 654"0-1458' + 136"° °1202'. B : Alfentanil infusion for 120 min during halothane anaesthesia. The curve is represented by the equation: C, = 81.4~°-2736' + 101.7-° °096'. c: Alfentanil bolus 60 ug kg"1 i.v. after xylazine—ketamine and halothane anaesthesia. A reasonable solution for this curve was not obtained.
ALTERED PHARMACOKINETICS OF ALFENTANIL IN HORSES
circulation from a site of sequestration, such as alteration or shift in tissue or protein binding or a change in vascular volume. As alpha2 agonists are known to have significant effects on sympathetic tone, it is postulated that there was initially an enlarged vascular volume (more rapid distribution) which then contracted as the effects of xylazine diminished. ACKNOWLEDGEMENTS This work was funded by the Equine Research Laboratory, University of California, Davis, with funds provided by the Oak Tree Racing Association and the State of California Satellite Wagering Fund. Jannsen Pharmaceutical kindly provided the alfentanil used in the study. The authors thank Jim Jacobs for the software used to drive the alfentanil infusion pump and Abbott Laboratories for the use of the computer and infusion pump.
REFERENCES 1. Kharasch ED, Hill FH, Eddy AC. Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism. Anesthesiology 1991; 75: 520-524. 2. Segal IS, Jarvis DJ, Duncan SR, White PF, Maze M. Clinical efficacy of oral-transdermal clonidine combinations during the perioperative period. Anesthesiology 1991; 74: 220-225. 3. Pascoe PJ, Black WD, Claxton JM, Sansom RE. The pharmacokinetics and locomotor activity of alfentanil in the horse. Journal of Veterinary Pharmacology and Therapeutics 1991; 14: 317-325. 4. White PF, Marietta MP, Pudwill CR, Way WL, Trevor AJ. Effects of halothane anesthesia on the biodisposition of ketamine in rats. Journal of Pharmacology and Experimental Therapeutics 1976; 196: 545-555. 5. Steffey EP, Pascoe PJ. Xylazine reduces the isoflurane MAC in horses. Veterinary Surgery 1991; 20: 158. 6. Salonen JS. Pharmacokinetics of medetomidine. Ada Veterinaria Scandmavica 1989; (Suppl. 85): 49-54.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 7, 2015
counted because of the time between administration of these drugs and administration of alfentanil (approximately 60 min). When inhalation agents are not given, a horse will stand up within 15-30 min of induction with xylazine-ketamine but it has been shown in other species that the elimination of ketamine, at least, is slowed by administration of halothane [4], and it has been shown that this dose of xylazine has an effect on the MAC of isoflurane in horses for about 4 h [5]. Although it is not possible to differentiate the effects of the two i.v. drugs in this study, evidence from other species suggests that xylazine is likely to have a modifying effect on the elimination of alfentanil. Dexmedetomidine was found to slow the hepatic metabolism of alfentanil but in the concentrations used it is unlikely that this effect is relevant clinically. That experiment showed that the threshold for inhibition of metabolism was approximately 0.2 \imol litre"1 or 47 ug ml"1 [1] and in a study in dogs receiving medetomidine 80 ug kg"1 i.v., the peak plasma concentration was about 35 ng ml"1 [6]. As clonidine has also been shown to alter the pharmacokinetics of alfentanil and there appears to be no effect on hepatic metabolism [1], the present experiment lends further evidence for an interaction between alfentanil and alpha2 adrenergic agonists. Our data indicate that metabolism was not affected, as the terminal elimination slopes were virtually identical when the concentration-time curve was past the plateau and the area under the curve was the same for both bolus treatments. Initially, alfentanil appeared to be undergoing greater distribution under the influence of xylazine-ketamine, as it reached smaller concentrations more rapidly. The plateau probably represents an input of the drug into the
347