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    Mean ± SD plasma dexmedetomidine concentration in 6 isoflurane-anesthetized cats following short-duration IV administration of dexmedetomidine hydrochloride (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]). Blood samples were obtained immediately prior to (data not shown) and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion.

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Pharmacokinetics of dexmedetomidine administered intravenously in isoflurane-anesthetized cats

André Escobar DVM, MS1, Bruno H. Pypendop DrMedVet, DrVetSci2, Kristine T. Siao BS3, Scott D. Stanley PhD4, and Jan E. Ilkiw BVSc, PhD5
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  • 1 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 2 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 3 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 4 K. L. Maddy Equine Analytical Chemistry Laboratory, California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 5 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

Abstract

Objective—To determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats.

Animals—6 healthy adult domestic female cats.

Procedures—Dexmedetomidine hydrochloride was injected IV (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in isoflurane-anesthetized cats. Blood samples were obtained immediately prior to and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion. Collected blood samples were transferred to tubes containing EDTA, immediately placed on ice, and then centrifuged at 3,901 × g for 10 minutes at 4°C. The plasma was harvested and stored at −20°C until analyzed. Plasma dexmedetomidine concentrations were determined by means of liquid chromatography–mass spectrometry. Dexmedetomidine plasma concentration-time data were fitted to compartmental models.

Results—A 2-compartment model with input in and elimination from the central compartment best described the disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats. Weighted mean ± SEM apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state were 402 ± 47 mL/kg and 1,701 ± 200 mL/kg, respectively; clearance and terminal half-life (harmonic mean ± jackknife pseudo-SD) were 6.3 ± 2.8 mL/min/kg and 198 ± 75 minutes, respectively. The area under the plasma concentration curve and maximal plasma concentration were 1,061 ± 292 min•ng/mL and 17.6 ± 1.8 ng/mL, respectively.

Conclusions and Clinical Relevance—Disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats was characterized by a moderate clearance and a long terminal half-life.

Abstract

Objective—To determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats.

Animals—6 healthy adult domestic female cats.

Procedures—Dexmedetomidine hydrochloride was injected IV (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in isoflurane-anesthetized cats. Blood samples were obtained immediately prior to and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion. Collected blood samples were transferred to tubes containing EDTA, immediately placed on ice, and then centrifuged at 3,901 × g for 10 minutes at 4°C. The plasma was harvested and stored at −20°C until analyzed. Plasma dexmedetomidine concentrations were determined by means of liquid chromatography–mass spectrometry. Dexmedetomidine plasma concentration-time data were fitted to compartmental models.

Results—A 2-compartment model with input in and elimination from the central compartment best described the disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats. Weighted mean ± SEM apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state were 402 ± 47 mL/kg and 1,701 ± 200 mL/kg, respectively; clearance and terminal half-life (harmonic mean ± jackknife pseudo-SD) were 6.3 ± 2.8 mL/min/kg and 198 ± 75 minutes, respectively. The area under the plasma concentration curve and maximal plasma concentration were 1,061 ± 292 min•ng/mL and 17.6 ± 1.8 ng/mL, respectively.

Conclusions and Clinical Relevance—Disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats was characterized by a moderate clearance and a long terminal half-life.

Dexmedetomidine hydrochloride is a widely used α2-adrenoreceptor agonist that causes sedation, analgesia, decreased anesthetic requirements, and cardiovascular depression in cats.1–3 The dextro enantiomer of medetomidine is responsible for the pharmacological activity of the racemic mixture; in most studies,4,5 the levo enantiomer appears inactive, at least at clinical doses. Therefore, as expected, equipotent doses of dexmedetomidine and medetomidine did not differ significantly with regard to subjective scores for sedation, analgesia, and muscle relaxation in cats.6,7

The mechanisms of action of the α2-adrenoreceptor agonists are related to the central activation of presynaptic α2-adrenoreceptors, which results in an inhibitory effect on noradrenaline release, and the stimulation of different postsynaptic, G-protein–coupled α2-adrenoreceptors, which result in peripheral vasoconstriction, analgesia and other effects.8 The initial increase in blood pressure caused by activation of peripheral α2-adrenoreceptors is temporary, and after the drug redistribution, this effect is balanced by the centrally mediated reduction in sympathetic activity.9,10

Reports of several studies1–3,6,7 of the use of dexmedetomidine in cats have been published. Similar to other α2-adrenoreceptor agonists, dexmedetomidine has been reported to decrease anesthetic requirements in some species, and therefore, it may be useful as an anesthetic adjunct.11–18 The pharmacokinetics of the drug in cats has not been reported, to our knowledge, thereby making recommendations on dosages and, in particular, dosing interval difficult. The purpose of the study reported here was to determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats.

Materials and Methods

Animals—Six adult healthy female cats were used in the study. The same 6 cats were used in 2 subsequent studies19,20 on the effects of dexmedetomidine on the MAC of isoflurane and the hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. Mean ± SD weight of the cats was 4.3 ± 1.2 kg; mean age was 1.5 years. Food and water were provided ad libitum to the cats during the study. This study was approved by the Institutional Animal Care and Use Committee at the University of California-Davis.

Instrumentation and drug administration—Each cat was anesthetized once in an acrylic chamber with isoflurane in oxygen. After endotracheal intubation, anesthesia was maintained via inhalation of isoflurane in oxygen delivered via a coaxial Mapleson F circuit. Oxygen flow was set at 200 mL/kg/min. Ventilation was spontaneous throughout the experiment. A 20-gauge, 48-mm cathetera was placed in a medial saphenous vein for fluid and drug administration, and another was placed in a jugular vein for blood sample collection. Prior to drug administration, the individual MAC was determined in each cat, as previously described.21,22 Briefly, after maintenance of constant end-tidal isoflurane concentration for 20 minutes, physiologic variables were measured and a 20-cm Martin forceps, closed to the first ratchet, was applied to the tail until gross purposeful movement was observed or 1 minute had elapsed. If gross purposeful movement was observed, the end-tidal isoflurane concentration was increased by 10%. If no movement was observed, the end-tidal isoflurane concentration was decreased by 10%. The stimulation was repeated after a 20-minute equilibrium period, and the MAC value was defined by the mean of 2 successive concentrations that allowed and prevented gross purposeful movement. Minimum alveolar concentration was determined in triplicate, and the mean value was calculated for each cat.

After the MAC had been determined for each cat, end-tidal isoflurane concentration was set at 0.7 times the individual's MAC; after an interval of 20 minutes, dexmedetomidine hydrochlorideb was administered IV via the medial saphenous catheter as a short-duration infusion (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]). A blood sample (2 mL) was collected from the jugular catheter before (data not included in pharmacokinetic analysis) and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes after starting dexmedetomidine administration. Each sample of blood was transferred to a tube containing EDTA, immediately placed on ice, and then centrifuged at 3,901 × g for 10 minutes at 4°C. The plasma was harvested and stored at −20°C until analyzed for dexmedetomidine concentrations.

Drug analysis—Following protein precipitation of the plasma samples, dexmedetomidine was quantitated via liquid chromatography–mass spectrometry analysis. The calibration standards were prepared as follows: stock solutions were made by dissolving 1.0 mg of dexmedetomidine hydrochloride standardc in 1.0 mL of methanol. Working solutions were prepared by dilution of the dexmedetomidine stock solution with methanol to concentrations of 10,000, 100, and 1 ng/mL. Plasma calibrators were prepared by dilution of the working dexmedetomidine solutions with drug-free feline plasma to concentrations of 0.25, 0.5, 1.0, 5.0, 10.0, 20.0, 50.0, and 100.0 ng/mL. Calibration curves and negative control samples were prepared fresh for each quantitative assay. In addition, quality-control samples (plasma fortified with analytes at concentrations equivalent to midpoint of the standard curve) were routinely included as an additional check of accuracy. The concentration of dexmedetomidine in each sample was determined by use of an internal standard (detomidine-D3)d method involving the peak area ratio and linear regression analysis. The targeted limit of quantification was 0.25 ng/mL.

Quantitative analyses were performed on a triple quadrupole mass spectrometere equipped with a heated electrospray ionization probe that was kept at 375°C. All analyses were performed in the positive ionization mode with spray voltage set at 4,000 V. The sheath, auxiliary, and ion sweep gas used was nitrogen at 45, 30, and 2 arbitrary units, respectively. The system was operated in the selected reaction-monitoring mode with argon as the collision gas at a pressure of 0.2 Pa (1.5 mTorr). The ion transfer tube was kept at 300°C; the scan time and width were 0.065 seconds and 0.1 m/z, respectively. Data were processed by use of a computer program.f The triple quadrupole mass spectrometer was coupled with a turbulent flow chromatography system.g The 50 × 0.5-mm columns used (particle size, 60 μm; pore size, 6 nm [60 Å]) were connected in tandem. Chromatographic separation used a 100 × 2.1-mm, 3-μm columnh and a linear gradient of acetonitrilei in water with a constant 0.2% formic acidj at a flow rate of 0.35 mL/min. The acetonitrile concentration was held at 10% for 0.3 minutes, then increased to 95% over 5.0 minutes. Prior to analysis, the plasma proteins, controls, and calibrators were extracted by precipitation with 0.5 mL of a 9:1 mixture of acetonitrile and 1M acetic acidk containing 10 ng of internal standard/mL, vortex mixed for 2.0 minutes, and refrigerated for 30.0 minutes, followed by centrifugation (1,864 × g for 3 minutes). The injection volumes were 50.0 μL.

Detection and quantitation used full-scan liquid chromatography–tandem mass spectrometry transitions of initial product ions for dexmedetomidine (m/z, 201.1). The response for the major product ion for dexmedetomidine (m/z, 95.1) was plotted, and the peak at the appropriate retention time was integrated by use of a computer program.f The concentration of dexmedetomidine in each sample (eg, calibrator, quality control, and unknown samples) was determined by use of an internal standard method involving the peak area ratio and linear regression analysis. The response for dexmedetomidine was linear and yielded correlation coefficients (R2) that were ≥ 0.99. The technique was optimized to provide a limit of quantitation at 0.25 ng/mL. Intraday accuracy (percentage of nominal concentration) was 95% for 1.0 ng/mL. Interday accuracy was 105% for 1.0 ng/mL. Intraday precision (ie, percentage relative SD) was 3.1% for 1.0 ng/mL. Interday precision was 7.0% for 1.0 ng/mL.

Pharmacokinetic analysis—All pharmacokinetic analyses were performed by use of a computer program.l Nonlinear least squares regression was performed on the plasma dexmedetomidine concentration-time data. Data were weighted by the reciprocal of the observed plasma dexmedetomidine concentrations and fitted to 1-, 2-, and 3-compartment models with zero-order input in and elimination from the central compartment. The appropriate model was selected by observation of the residuals plot and by use of the Akaike information criterion.23,24

Parameters estimated by use of the compartmental model were apparent volume of the central compartment, apparent volume of the peripheral compartment, distributional clearance, and clearance. Other pharmacokinetic parameters were calculated by use of standard pharmacokinetic equations.25 Normal distribution of pharmacokinetic parameters was assessed by use of the Shapiro-Wilk test. Data are reported as weighted mean ± SEM and range, although half-lives and clearances are presented as harmonic mean ± jackknife pseudo-SD and range,26,27 unless specified otherwise. To improve the precision of the mean estimates, individual parameters used to calculate means were weighted by the reciprocal of their variance (obtained via the nonlinear regression procedure).28

Results

For the 6 cats, the mean isoflurane MAC was 2.07 ± 0.10%. A 2-compartment model best described the changes in plasma dexmedetomidine concentration following a 5-minute IV infusion of the drug (10 μg/kg [rate, 2 μg/kg/min]; Figure 1). The apparent volume of distribution of the central compartment, VSS, clearance, and terminal half-life were 402 ± 47 mL/kg (range, 311 to 606 mL/kg), 1,701 ± 200 mL/kg (range, 1,373 to 2,551 mL/kg), 6.3 ± 2.8 mL/min/kg (range, 4.5 to 13.9 mL/min/kg), and 198 ± 75 minutes (range, 129 to 295 minutes), respectively. The area under the plasma concentration curve and Cmax were 1,061 ± 292 min•ng/mL (range, 720 to 2,233 min•ng/mL) and 17.6 ± 1.8 ng/mL (range, 12.9 to 24.2 ng/mL), respectively. The pharmacokinetic parameters for dexmedetomidine in cats were summarized (Table 1).

Figure 1—
Figure 1—

Mean ± SD plasma dexmedetomidine concentration in 6 isoflurane-anesthetized cats following short-duration IV administration of dexmedetomidine hydrochloride (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]). Blood samples were obtained immediately prior to (data not shown) and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion.

Citation: American Journal of Veterinary Research 73, 2; 10.2460/ajvr.73.2.285

Table 1—

Pharmacokinetic parameters for dexmedetomidine following short-duration IV administration of dexmedetomidine hydrochloride (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in 6 isoflurane-anesthetized cats.

ParameterMean ± SEM (range)
A (ng/mL)18.6 ± 2.2 (12.6–26.0)
B (ng/mL)3.7 ± 0.5 (2.8–6.1)
α (min−1)0.1038 ± 0.0178 (0.07–0.1680)
β (min−1)0.0029 ± 0.0005 (0.0023–0.0054)
t1/2α (min)*5.4 ± 1.8 (4.1–9.9)
t1/2β (min)*198 ± 75 (129–295)
K10 (/min)0.0130 ± 0.0036 (0.0082–0.0336)
K10 t1/2 (min)44.2 (20.2–84.2)
K12 (/min)0.0679 ± 0.0137 (0.0441–0.1220)
K21 (/min)0.0213 ± 0.0033 (0.0176–0.0376)
V1 (mL/kg)402 ± 47 (311–606)
V2 (mL/kg)1,291 ± 187 (1,016–2,104)
VSS (mL/kg)1,701 ± 200 (1,373–2,551)
Clearance (mL/min/kg)*6.3 ± 2.8 (4.5–13.9)
Cld (mL/min/kg)*32.8 ± 17.6 (17.9–54.3)
AUC (min•ng/mL)1,061 ± 292 (720–2,233)
Cmax (ng/mL)17.6 ± 1.8 (12.9–24.2)

Value reported as harmonic mean ± jackknife-pseudo SD.

Values are median (range) because the parameter data were not normally distributed.

A and B = Coefficients. α and β = Exponents in the equation Ct = Ae−αt + Be−βt, where Ct is the dexmedetomidine concentration at time t. AUC = Area under the plasma concentration curve. Cld = Distributional clearance. K10, K12, and K21 = Rate constants. t1/2α = Distribution half-life. t1/2β = Elimination half-life. V1 = Apparent volume of the central compartment. V2 = Apparent volume of the peripheral compartment.

Discussion

Because of its high affinity and selectivity for α2-adrenoreceptors and possibly a longer-acting analgesic effect, dexmedetomidine has been considered a substitute for xylazine and medetomidine in veterinary medicine.10,29 Despite the broad use of dexmedetomidine in cats, to the authors' knowledge, no information regarding the pharmacokinetics of dexmedetomidine in this species has been published. α2-Adrenoreceptor agonists have been used in various species to decrease anesthetic requirements.11–18 In that context, it is necessary to obtain pharmacokinetic data in anesthetized animals because inhalation anesthetic agents affect the pharmacokinetics of drugs administered concurrently.30,31 The present study has provided information necessary for the rational design of protocols for IV administration of dexmedetomidine in cats anesthetized with an inhalation anesthetic agent.

In the present study, a 2-compartment model best described the disposition of dexmedetomidine when administered as a short-duration IV infusion, which is in agreement with data obtained from rats.32 Cardiovascular effects, such as bradycardia and vasoconstriction, caused by dexmedetomidine likely cause changes in distribution and elimination of the drug; therefore, the results reported here should be interpreted in the context of the dose administered. In 1 study,10 bradycardia and vasoconstriction developed in dogs even at low plasma dexmedetomidine concentrations (2.0 ng/mL). An increase in mean arterial pressure of 37% and a decrease in heart rate of 35% were evident in rats after a short-duration infusion of 30 μg of dexmedetomidine/kg.32 In another study,33 humans in whom the plasma dexmedetomidine concentration was 1.2 ng/mL had an observed 19% decrease in cardiac output, which resulted in a 12% decrease in drug clearance.

Investigations of the pharmacokinetics of dexmedetomidine administered IV (1 μg/kg over 5 minutes) in children < 2 years old and children between 2 and 11 years old have revealed larger clearances (17.4 and 17.3 mL/kg/min, respectively) and VSS (3,800 and 2,200 mL/kg, respectively) and shorter elimination half-lives (139 and 96 minutes, respectively),34 compared with those determined in cats after short-duration IV infusion of 10 μg of dexmedetomidine/kg in the present study. Similarly, in rats,32 the values of clearance (59.4 mL/kg/min) and VSS (3,240.0 mL/kg) were larger and the elimination half-life was shorter (57.4 minutes) after short-duration infusion of 30 μg of dexmedetomidine/kg, compared with the findings in the cats in the present study. α2-Adrenoreceptor agonists are metabolized by the liver and excreted in urine.35 Low activity of 1 cytochrome P450 subfamily36 and deficiency in glucuronide conjugation cats37,38 could be the causes of the lower clearance and longer elimination half-life of dexmedetomidine, compared with findings in other species. In addition, cats in the present study were anesthetized with isoflurane, unlike the humans and rats in the other studies that remained conscious during the experiments, and isoflurane is expected to decrease clearance and volume of distribution.30,31 Finally, the higher dose of dexmedetomidine used in the present study, compared with that used in the study34 in children, may have resulted in more profound cardiovascular alterations, possibly resulting in a smaller volume of distribution and lower clearance.

In 1 study10 in dogs, the clearance and the terminal half-life of dexmedetomidine were 16.16 mL/min/kg and 39.6 minutes, respectively, after an IV bolus of 10 μg/kg. However, in dogs that received a 24-hour infusion of dexmedetomidine and were anesthetized with isoflurane during the first 2 hours of the infusion, the elimination half-life was 28 minutes.39 Compared with dogs, cats appear to have lower clearance and longer terminal half-life of dexmedetomidine. However, in both dog studies,10,39 blood samples were collected for 2 hours after the end of dexmedetomidine administration, and it is possible that what was considered to be the elimination phase actually was a distribution or a mixed distribution and elimination phase.

After the IV infusion, the Cmax for dexmedetomidine ranged from 12.9 to 24.2 ng/mL in the cats in the present study. These values are similar to the plasma dexmedetomidine concentration of 12.2 ng/mL detected after IM injection of 10 μg of dexmedetomidine/kg followed by a continuous IV infusion of dexmedetomidine (0.25 μg/kg/min) in cats.7 In rats, after a 10-minute infusion of 30 μg of dexmedetomidine/kg, the mean plasma concentration of the drug was 16.7 ng/mL.32 After IV administration of a dexmedetomidine bolus of 1 μg/kg followed by a 24-hour infusion at a rate of 1 μg/kg/h in dogs that were anesthetized with isoflurane or propofol during the first 2 hours of the infusion, the Cmax was 0.7 and 0.57 ng/mL, respectively.39 These differences may be due to differences in study design, to dose-dependent pharmacokinetics, or to differences in volume of distribution.

The results of the present study should be interpreted in view of 2 main limitations. First, the disposition of dexmedetomidine was studied in isoflurane-anesthetized cats, and isoflurane has been reported to alter the disposition of drugs administered concurrently.30,31 Therefore, the results apply only to cats anesthetized with an inhalation anesthetic agent. Moreover, although the isoflurane concentration was reduced to 0.7 times the individual cat's MAC prior to dexmedetomidine administration, this resulted in an unknown depth of anesthesia because the effect of dexmedetomidine administered IV on MAC in cats has not been reported, to our knowledge. It is likely that the anesthetic depth varied during the pharmacokinetic evaluation because the MAC-reducing effect of α2-adrenoreceptor agonists is plasma concentration dependent.14 Second, a single dose of dexmedetomidine was investigated, and it is likely that dexmedetomidine has dose-dependent pharmacokinetics because of the dose-dependent cardiovascular effects expected with α2-adrenoreceptor agonists.40,41 Nevertheless, the data obtained in the present study have suggested that the disposition of dexmedetomidine in cats is characterized by a moderate clearance and a long terminal half-life.

ABBREVIATIONS

Cmax

Maximal plasma concentration

MAC

Minimum alveolar concentration

m/z

Mass-to-charge ratio

VSS

Apparent volume of distribution at steady state

a.

Central Venous Catheterization set, Arrow International, Reading, Pa.

b.

Dexdomitor, Pfizer, New York, NY.

c.

Provided by the Orion Corp, Espoo, Finland.

d.

Frontier BioPharm, Richmond, Ky.

e.

TSQ Vantage, Thermo Scientific, San Jose, Calif.

f.

LCQuan software, version 2.6, Thermo Scientific, San Jose, Calif.

g.

Aria TLX-4, Thermo Fisher Scientific, Franklin, Mass.

h.

ACE C18, Mac Mod, Chadds Ford, Pa.

i.

High-performance liquid chromatography–grade acetonitrile, Burdick and Jackson, Muskegon, Mich.

j.

Spectrophotometric grade formic acid, Sigma-Aldrich, St Louis, Mo.

k.

High-performance liquid chromatography–grade acetic acid, Thermo Fisher Scientific, Franklin, Mass.

l.

WinNonlin Pro, version 5.2, Pharsight, Cary, NC.

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Contributor Notes

Dr. Escobar's present address is Department of Veterinary Clinics and Surgery, Faculdade de Ciências Agrárias e Veterinárias, São Paulo State University, Jaboticabal, SP 14884-900, Brazil.

Funded by the Center for Companion Animal Health, School of Veterinary Medicine, University of California-Davis; and the Orion Corporation.

Dr. Escobar received a research internship grant funding from the CAPES Foundation, Brazil.

Address correspondence to Dr. Pypendop (bhpypendop@ucdavis.edu).