Pharmacokinetics of dexmedetomidine after intravenous administration of a bolus to cats

Bruno H. Pypendop Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Jan E. Ilkiw Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Abstract

Objective—To characterize the pharmacokinetics of dexmedetomidine after IV administration of a bolus to conscious healthy cats.

Animals—5 healthy adult spayed female cats.

Procedures—Dexmedetomidine was administered IV as a bolus at 3 doses (5, 20, or 50 μg/kg) on separate days in a random order. Blood samples were collected immediately before and at various times for 8 hours after drug administration. Plasma dexmedetomidine concentrations were determined with liquid chromatography–mass spectrometry. Compartment models were fitted to the concentration-time data by means of nonlinear regression.

Results—A 2-compartment model best fit the concentration-time data after administration of 5 μg/kg, whereas a 3-compartment model best fit the data after administration of 20 and 50 μg/kg. The median volume of distribution at steady-state and terminal half-life were 371 mL/kg (range, 266 to 435 mL/kg) and 31.8 minutes (range, 30.3 to 39.7 minutes), respectively, after administration of 5 μg/kg; 545 mL/kg (range, 445 to 998 mL/kg) and 56.3 minutes (range, 39.3 to 68.9 minutes), respectively, after administration of 20 μg/kg; and 750 mL/kg (range, 514 to 938 mL/kg) and 75.3 minutes (range, 52.2 to 223.3 minutes), respectively, after administration of 50 μg/kg.

Conclusions and Clinical Relevance—The pharmacokinetics of dexmedetomidine was characterized by a small volume of distribution and moderate clearance and had minimal dose dependence within the range of doses evaluated. These data will help clinicians design dosing regimens once effective plasma concentrations are established.

Abstract

Objective—To characterize the pharmacokinetics of dexmedetomidine after IV administration of a bolus to conscious healthy cats.

Animals—5 healthy adult spayed female cats.

Procedures—Dexmedetomidine was administered IV as a bolus at 3 doses (5, 20, or 50 μg/kg) on separate days in a random order. Blood samples were collected immediately before and at various times for 8 hours after drug administration. Plasma dexmedetomidine concentrations were determined with liquid chromatography–mass spectrometry. Compartment models were fitted to the concentration-time data by means of nonlinear regression.

Results—A 2-compartment model best fit the concentration-time data after administration of 5 μg/kg, whereas a 3-compartment model best fit the data after administration of 20 and 50 μg/kg. The median volume of distribution at steady-state and terminal half-life were 371 mL/kg (range, 266 to 435 mL/kg) and 31.8 minutes (range, 30.3 to 39.7 minutes), respectively, after administration of 5 μg/kg; 545 mL/kg (range, 445 to 998 mL/kg) and 56.3 minutes (range, 39.3 to 68.9 minutes), respectively, after administration of 20 μg/kg; and 750 mL/kg (range, 514 to 938 mL/kg) and 75.3 minutes (range, 52.2 to 223.3 minutes), respectively, after administration of 50 μg/kg.

Conclusions and Clinical Relevance—The pharmacokinetics of dexmedetomidine was characterized by a small volume of distribution and moderate clearance and had minimal dose dependence within the range of doses evaluated. These data will help clinicians design dosing regimens once effective plasma concentrations are established.

Dexmedetomidine is an agonist of α2-adrenoceptors that causes sedation, analgesia, and cardiovascular depression.1–3 The pharmacokinetics of dexmedetomidine in isoflurane-anesthetized cats has been reported in another study4 conducted by our research group. However, anesthesia with isoflurane can influence the disposition of drugs administered concurrently5,6; therefore, the results of that previous study4 are likely applicable only to cats anesthetized with an inhalation anesthetic. To the authors’ knowledge, the pharmacokinetics of dexmedetomidine in conscious cats has not been reported. The objective of the study reported here was to characterize the pharmacokinetics of dexmedetomidine after IV administration of a bolus at each of 3 doses to conscious cats. We hypothesized that dexmedetomidine would have dose-dependent pharmacokinetics in conscious cats.

Materials and Methods

Animals—Five healthy 1- to 2-year-old spayed female cats (mean ± SD body weight, 4.6 ± 0.5 kg) were used in the study. The study was approved by the Institutional Animal Care and Use Committee at the University of California-Davis.

Implantation of a vascular access port—Prior to the study, each cat was anesthetized and a vascular access port was implanted, with the catheter in a carotid artery and the port located in the subcutaneous tissues between the scapulae. Briefly, cats were administered buprenorphine (20 μg/kg, IV) and cefazolin (22 mg/kg, IV). Anesthesia was induced and maintained with isoflurane in oxygen. A skin incision was made over the jugular furrow, the subcutaneous tissue was dissected, and the sternomastoid and sternohyoid muscles were separated by blunt dissection. The carotid artery was exposed and separated from the vagus nerve. A second skin incision was made between the scapulae, and the subcutaneous tissue was dissected. A tunnel between the 2 skin incisions was created by blunt insertion of a forceps through the subcutaneous tissues on the lateral aspect of the neck. The vascular access port was inserted in the incision between the scapulae, and the catheter was guided through the tunnel in the subcutaneous tissues until its tip was in close proximity to the carotid artery. A small incision was made in the carotid artery with a 22-gauge hypodermic needle, and approximately 5 cm of the catheter was inserted in the carotid artery. The artery was ligated around the catheter. Blood was aspirated through the port and catheter assembly, and the port and catheter were filled with heparin (1,000 U/mL). Incisions were closed in 2 layers (subcutaneous and subcuticular) with absorbable suture material. Carprofen (4 mg/kg) was administered SC, and cats were allowed to recover from anesthesia. Cats were observed until they were able to walk without ataxia. Signs of pain were assessed approximately 4 hours later and then once daily for 10 days. The study did not commence until completion of the postoperative observations (ie, > 10 days after surgical implantation of the vascular access port). The vascular access port was used for collection of blood samples. Patency of the port was maintained by filling the volume of the port and catheter with heparin (1,000 U/mL) 3 times/wk.

Drug administration—On the day of an experiment, a 22-gauge, 25-mm catheter was inserted into a cephalic vein; this catheter was used for drug administration. Dexmedetomidine hydrochloride at each of 3 doses (5, 20, or 50 μg/kg) was administered IV as a bolus. In addition, because the results reported here were part of a larger study7 on the effects of dexmedetomidine on the thermal threshold, acepromazine maleate (0.1 mg/kg) or saline (0.9% NaCl) solution was administered as a positive control for sedation and a negative control for sedation, respectively. All drugs were diluted with saline solution to a total volume of 1 mL. All cats received all treatments in a random order (determined by a computer-generated list). Each treatment was administered on a separate day; there was at least 2 weeks between successive treatments. Thermal threshold was measured before drug administration; 5, 20, 35, 50, and 65 minutes after drug administration; and then at hourly intervals until 8 hours after drug administration.

Collection of blood samples—Blood samples (2 mL) were collected from the vascular access port before (time 0) and 1, 2, 4, 8, 15, 30, 60, 120, 240, and 480 minutes after drug administration. Blood was transferred to tubes containing EDTA; tubes were immediately placed on ice and then centrifuged for 10 minutes at 3,901 × g at 4°C within 10 minutes after collection. Plasma was separated and stored frozen at −20°C until analysis for determination of the dexmedetomidine concentration.

The vascular access port did not remain patent throughout the study in 3 cats (2 dexmedetomidine treatments in 1 cat and 1 dexmedetomidine treatment in each of 2 other cats). Thus, an alternate route for blood collection was established on the day before administration of the dexmedetomidine treatments to these cats. Briefly, the cats were anesthetized with isoflurane in oxygen. A 24-gauge, 12-cm catheter was placed in a jugular vein, capped with an infusion plug, and sutured to the skin. Cats were then allowed to recover from anesthesia. The catheter in the jugular vein was used for collection of blood samples. The catheter for drug administration in these cats was placed in a medial saphenous vein, rather than a cephalic vein.

Dexmedetomidine analysis—Dexmedetomidine concentration was quantified in protein-precipitated plasma samples by means of liquid chromatography–mass spectrometry performed in accordance with a previously reported technique.4 Detomidine-D3 was used as the internal standard. The technique was optimized to provide a limit of quantitation of 0.1 ng/mL. To verify accuracy and precision of the assay, quality control samples (feline plasma spiked with known concentrations of dexmedetomidine standardaa) were included in the analysis; the quality control samples were at each of 3 concentrations (0.4, 5, and 30 ng/mL). Measurement of the concentration in these quality control samples was repeated 5 times. The mean and SD were calculated. Accuracy was calculated as the ratio between the mean measured concentration in the quality control samples and the actual dexmedetomidine concentration in the quality control samples. Imprecision was calculated as the ratio of the SD and the mean concentration. Accuracy (percentage nominal concentration) ranged from 91% to 93%, 98% to 105%, and 90% to 98% for the concentrations of 0.4, 5, and 30 ng/mL, respectively. Intraday imprecision (percentage relative SD) ranged from 2% to 9%, 2% to 3%, and 3% to 7% for the concentrations of 0.4, 5, and 30 ng/mL, respectively. Interday imprecision was 1.9%, 4.8%, and 6.1% for the concentrations of 0.4, 5, and 30 ng/mL, respectively. Accuracy > 85% and imprecision < 15% were considered acceptable.

Pharmacokinetic analysis—Nonlinear least squares regression was performed with the aid of a computer programb on the plasma dexmedetomidine concentrations measured after IV administration of 5, 20, or 50 μg/kg. Two- and 3-compartment models (with input in and first-order elimination from the central compartment) were fitted to the data. Data were weighted by the value of (1/predicted concentration2). Observation of the residuals plot and Akaike information criterion were used to select the model that best fit the data.8

For the 2-compartment model, the drug disposition curve was described by the following biexponential equation:

article image

where Conct is the plasma drug concentration as a function of time t (minutes after dexmedetomidine administration); A and B are the y-intercepts of extrapolated lines for the distribution and elimination portions of the curve, respectively; e is the base of the natural logarithm; and α and β are the slopes associated with the distribution and elimination portions of the curve, respectively.

For the 3-compartment model, the drug disposition curve was described by the following triexponential equation:

article image

where A, B, and C are the y-intercepts of extrapolated lines for the fast distribution, slow distribution, and elimination portions of the curve, respectively, and α, β, and γ are the slopes associated with the fast distribution, slow distribution, and elimination portions of the curve, respectively. The pharmacokinetic parameters estimated by the model (A, B, C, α, β, and γ) were then used to calculate other pharmacokinetic parameters for each cat by the use of standard pharmacokinetic equations.9

Normal distribution of pharmacokinetic parameters was verified by means of the Shapiro-Wilk test. Because some parameters were not normally distributed and because of the small sample size, parameters were compared by means of Wilcoxon signed rank tests to examine whether the disposition of dexmedetomidine was dose dependent within the dose range evaluated. Bonferroni correction for multiple comparisons was applied. Parameters related to the dose (A, B, C, concentration at time 0, area under the concentration-time curve, and area under the first moment curve) were indexed to their respective dose for analysis. Significance was set at values of P < 0.05. Plasma concentration data were reported as mean ± SD, and pharmacokinetic parameters were reported as median and range.

Results

Of the 15 concentration-time profiles, 11 were obtained from analysis of arterial blood samples and 4 from analysis of venous blood samples. Visual inspection of the concentration-time data did not reveal obvious differences between profiles obtained from arterial and venous blood, and pharmacokinetic parameters from all profiles were included for the calculation of descriptive statistics and dose comparisons.

Plasma dexmedetomidine concentration decreased to below the limit of quantitation (0.1 ng/mL) before the 240-minute sample in all cats after administration of 5 μg/kg and before the 480-minute sample in all cats after administration of 20 μg/kg. It remained above the limit of quantitation for the full duration of the study after administration of 50 μg/kg, except for 1 cat, in which it was lower than the limit of quantitation at 480 minutes.

A 2-compartment model best described the decrease in plasma dexmedetomidine concentration after IV administration of 5 μg/kg, whereas a 3-compartment model best described the decrease in plasma dexmedetomidine concentration after IV administration of 20 and 50 μg/kg (Figure 1). Pharmacokinetic parameters for IV administration of a bolus dose of 5, 20, and 50 μg/kg of dexmedetomidine were summarized (Table 1). No significant difference among doses was detected.

Figure 1—
Figure 1—

Mean ± SD plasma dexmedetomidine concentration over time after IV administration of a bolus at a dose of 5 μg/kg (circles), 20 μg/kg (triangles), or 50 μg/kg (diamonds) to 5 cats. Plasma dexmedetomidine concentration decreased to below the limit of quantitation (0.1 ng/mL) before the 240-minute sample in all cats after administration of 5 μg/kg and before the 480-minute sample in all cats after administration of 20 μg/kg.

Citation: American Journal of Veterinary Research 75, 5; 10.2460/ajvr.75.5.441

Table 1—

Median (range) values for pharmacokinetic parameters of dexmedetomidine after IV administration of a bolus at a dose of 5, 20, or 50 μg/kg to 5 cats.

Parameter5 μg/kg20 μg/kg50 μg/kg
A (ng/mL)57.3 (6.7–70.4)67.2 (26.3–566.5)437.3 (187.5–899.9)
B (ng/mL)8.0 (5.5–10.9)34.7 (18.2–69.4)68.1 (40.3–129.2)
C (ng/mL)NA9.3 (1.9–18.3)12.8 (2.2–24.7)
α (min−1)0.307 (0.086–0.526)0.508 (0.290–1.530)0.482 (0.291–0.641)
β (min−1)0.022 (0.017–0.023)0.056 (0.027–0.173)0.048 (0.021–0.121)
γ (min−1)NA0.012 (0.010–0.018)0.009 (0.003–0.013)
Rapid distribution half-life (min)2.3 (1.3–8.0)1.4 (0.5–2.4)1.4 (1.1–2.4)
Slow distribution half-life (min)NA12.3 (4.0–25.6)14.4 (5.7–33.8)
Terminal half-life (min)31.8 (30.3–39.7)56.3 (39.3–68.9)75.3 (52.2–223.3)
V1 (mL)80 (64–284)223 (31–318)85 (50–211)
V2 (mL)191 (94–292)167 (58–278)225 (72–345)
V3 (mL)NA350 (60–497)420 (337–426)
Vss (mL)371 (266–435)545 (445–998)750 (514–938)
Concentration at time 0 (ng/mL)62.8 (17.6–78.0)89.6 (62.9–645.2)591.2 (237.4–1,000.6)
Clearance (mL/min/kg)9.2 (9.2–10.0)12.8 (9.0–24.3)13.9 (10.6–17.9)
First distribution clearance (mL/min/kg)11.8 (5.2–50.8)29.9 (16.3–49.9)19.3 (13.6–31.2)
Second distribution clearance (mL/min/kg)NA8.6 (0.7–15.2)5.6 (1.5–10.6)
Elimination half-life (min)5.7 (4.8–21.0)6.4 (1.6–19.9)4.8 (3.3–8.1)
k10 (min−1)0.121 (0.033–0.143)0.109 (0.035–0.432)0.144 (0.085–0.213)
k12 (min−1)0.156 (0.019–0.184)0.192 (0.094–0.65)0.233 (0.125–0.271)
k21 (min−1)0.056 (0.043–0.335)0.28 (0.144–0.311)0.106 (0.056–0.249)
k13 (min−1)NA0.042 (0.002–0.413)0.042 (0.02–0.126)
k31 (min−1)NA0.019 (0.011–0.044)0.013 (0.004–0.025)
AUC (ng•min/mL)542 (500–546)1,558 (824–2,211)3,606 (2,787–4,708)
AUC/dose (min•kg/mL)0.002 (0.001–0.002)0.002 (0.001–0.003)0.001 (0.001–0.003)
AUMC (ng•min2/mL)18,575 (15,850–22,835)60,533 (33,862–143,964)168,995 (145,636–351,478)
Mean residence time (min)37.1 (29.0–44.6)41.1 (33.7–65.1)50.3 (41.6–76.9)

In a 3-compartment model, the predicted plasma dexmedetomidine concentration at time t was calculated as Conct = Ae−αt + Be−βt + Ce−γt, where A, B, and C are the y-intercepts of extrapolated lines for the fast distribution, slow distribution, and elimination portions of the curve, respectively, and α, β, and γ are the slopes associated with the fast distribution, slow distribution, and elimination portions of the curve, respectively.

AUC = Area under the concentration-time curve. AUMC = Area under the first moment curve. k10 = Microrate constant for elimination of drug from the central compartment to outside the body. k12 = Microrate constant for transfer of drug from the central compartment to the first peripheral compartment. k13 = Microrate constant for transfer of drug from the central compartment to the second peripheral compartment. k21 = Microrate constant for transfer of drug from the first peripheral compartment to the central compartment. k31 = Microrate constant for transfer of drug from the second peripheral compartment to the central compartment. NA = Not applicable. V1 = Volume of the central compartment. V2 = Volume of the first peripheral compartment. V3 = Volume of the second peripheral compartment. Vss = Volume of distribution at steady state.

Discussion

The purpose of the study reported here was to determine the pharmacokinetics of dexmedetomidine after IV administration of a bolus to cats. Overall, the pharmacokinetics of dexmedetomidine was characterized by a small volume of distribution and moderate clearance, which resulted in a short terminal half-life.

A vascular access port had been implanted in each cat to allow access to a carotid artery and collection of arterial blood samples. Analysis of the arterial drug concentration is preferred for pharmacokinetic studies, particularly if concentrations are to be related to the effect, given that for most drugs, arterial concentrations represent the input to the site of effect and are not dependent on the sampling site.10 However, because blood samples could not be collected from the vascular access port, jugular venous blood was collected instead of arterial blood for 4 of 15 collections and used to determine concentration-time profiles. The effect of the use of venous blood on the pharmacokinetic parameters is unknown; however, visual comparison of the venous and arterial profiles did not reveal obvious differences. Therefore, the 4 venous profiles were included in the descriptive statistics of the parameter estimates and in the dose comparisons.

A 2-compartment model best fit the plasma dexmedetomidine concentration-time data after administration of 5 μg/kg, whereas a 3-compartment model best fit the data after administration of 20 and 50 μg/kg. This likely was related to the fact that plasma dexmedetomidine concentrations decreased to below the lower limit of quantitation (0.1 ng/mL) of the assay between the samples collected at 120 and 240 minutes for the 5 μg/kg dose, whereas concentrations were higher than the limit of quantitation for > 240 minutes after administration of 20 μg/kg and for the full duration of the experiment (480 minutes) after administration of 50 μg/kg. The inability to quantify plasma dexmedetomidine concentrations for > 120 minutes after administration of the lowest dose likely resulted in poor characterization of the elimination phase. Thus, estimates related to the terminal phase should be interpreted with caution for the 5 μg/kg dose. For example, the terminal half-life appears shorter for that dose than for the other doses, which again may be related to incomplete characterization of the terminal phase.

Medetomidine and its functionally useful stereoisomer, dexmedetomidine, cause dose- or concentration-dependent cardiovascular effects, mainly characterized by a decrease in heart rate and an increase in systemic vascular resistance and a subsequent decrease in blood flow.3,11–13 Because dexmedetomidine is likely cleared mainly by hydroxylation in the liver, the effect of dexmedetomidine on blood flow is expected to influence its disposition in a concentration-dependent manner.14–17 Administration of atipamezole, an α2-adrenoceptor antagonist, to dogs increases the clearance of medetomidine, presumably by antagonizing the decrease in cardiac output.18 Similarly, MK-467, a peripheral α2-adrenoceptor antagonist, increases the clearance of dexmedetomidine in dogs, presumably by the same mechanism.19 The design of the present study did not allow us to directly assess a possible effect of changes in plasma dexmedetomidine concentration on clearance; however, if there were a substantial effect, dose-dependent pharmacokinetics would be expected, considering that both magnitude and duration of the cardiovascular effects would be larger at the higher doses. Comparison of pharmacokinetic parameters for the 3 doses suggested minimal dose dependence.

Sample size in the present study was small (n = 5), and all cats were healthy young adult spayed females. Therefore, results of this study may not be representative of the entire cat population. In addition, the small sample size may have limited the statistical power for some dose comparisons. However, the pharmacokinetics of dexmedetomidine after IV administration of a bolus of 5, 20, and 50 μg/kg in cats was characterized by a small volume of distribution and moderate clearance with minimal dose dependence.

a.

Provided by Orion Pharma, Turku, Finland.

b.

WinNonlin, version 6.2, Certara, St Louis, Mo.

References

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    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Monteiro ER, Campagnol D, Parrilha LR, et al. Evaluation of cardiorespiratory effects of combinations of dexmedetomidine and atropine in cats. J Feline Med Surg 2009; 11: 783792.

    • Crossref
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  • 3. Pypendop BH, Barter LS, Stanley SD, et al. Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. Vet Anaesth Analg 2011; 38: 555567.

    • Crossref
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    • Export Citation
  • 4. Escobar A, Pypendop BH, Siao KT, et al. Pharmacokinetics of dexmedetomidine administered intravenously in isoflurane-anesthetized cats. Am J Vet Res 2012; 73: 285289.

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    • Crossref
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    • Export Citation
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  • Figure 1—

    Mean ± SD plasma dexmedetomidine concentration over time after IV administration of a bolus at a dose of 5 μg/kg (circles), 20 μg/kg (triangles), or 50 μg/kg (diamonds) to 5 cats. Plasma dexmedetomidine concentration decreased to below the limit of quantitation (0.1 ng/mL) before the 240-minute sample in all cats after administration of 5 μg/kg and before the 480-minute sample in all cats after administration of 20 μg/kg.

  • 1. Slingsby LS, Taylor PM. Thermal antinociception after dexmedetomidine administration in cats: a dose-finding study. J Vet Pharmacol Ther 2008; 31: 135142.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Monteiro ER, Campagnol D, Parrilha LR, et al. Evaluation of cardiorespiratory effects of combinations of dexmedetomidine and atropine in cats. J Feline Med Surg 2009; 11: 783792.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Pypendop BH, Barter LS, Stanley SD, et al. Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. Vet Anaesth Analg 2011; 38: 555567.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Escobar A, Pypendop BH, Siao KT, et al. Pharmacokinetics of dexmedetomidine administered intravenously in isoflurane-anesthetized cats. Am J Vet Res 2012; 73: 285289.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Thomasy SM, Pypendop BH, Ilkiw JE, et al. Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isoflurane-anesthetized cats. Am J Vet Res 2005; 66: 11621166.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Pypendop BH, Brosnan RJ, Siao KT, et al. Pharmacokinetics of remifentanil in conscious cats and cats anesthetized with isoflurane. Am J Vet Res 2008; 69: 531536.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Pypendop BH, Ilkiw JE. Relationship between plasma dexmedetomidine concentration and sedation score and thermal threshold in cats. Am J Vet Res 2014; 75: 446452.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Yamaoka K, Nakagawa T, Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 1978; 6: 165175.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Gabrielsson J, Weiner D. Pharmacokinetic concepts. In: Gabrielsson J, Weiner D, eds. Pharmacokinetic and pharmacodynamic data analysis: concepts and applications. 4th ed. Stockholm: Swedish Pharmaceutical Press, 2006; 11224.

    • Search Google Scholar
    • Export Citation
  • 10. Jacobs JR, Nath PA. Compartment model to describe peripheral arterial-venous drug concentration gradients with drug elimination from the venous sampling compartment. J Pharm Sci 1995; 84: 370375.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Lamont LA, Bulmer BJ, Grimm KA, et al. Cardiopulmonary evaluation of the use of medetomidine hydrochloride in cats. Am J Vet Res 2001; 62: 17451749.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Golden AL, Bright JM, Daniel GB, et al. Cardiovascular effects of the α2-adrenergic receptor agonist medetomidine in clinically normal cats anesthetized with isoflurane. Am J Vet Res 1998; 59: 509513.

    • Search Google Scholar
    • Export Citation
  • 13. Lawrence CJ, Prinzen FW, de Lange S. The effect of dexmedetomidine on nutrient organ blood flow. Anesth Analg 1996; 83: 11601165.

  • 14. Salonen JS. Tissue-specificity of hydroxylation and N-methylation of arylalkylimidazoles. Pharmacol Toxicol 1991; 69: 14.

  • 15. Kaivosaari S, Salonen JS, Taskinen J. N-glucuronidation of some 4-arylalkyl-1H-imidazoles by rat, dog, and human liver microsomes. Drug Metab Dispos 2002; 30: 295300.

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