Pharmacokinetics of butorphanol after intravenous, intramuscular, and oral administration in Hispaniolan Amazon parrots (Amazona ventralis).
Key words: pharmacokinetics, analgesia, opioid, butorphanol, avian, psittacine, Hispaniolan Amazon parrot, Amazona ventralis
Psittacine species are frequently presented to veterinarians for conditions requiring analgesia, such as traumatic injuries or surgical procedures. However, limited results are available from controlled studies of appropriate opioid dosages and dosing frequencies for any avian species. The lack of information detailing dose-response characteristics and dosing intervals for analgesic agents has compelled veterinarians who treat birds to extrapolate information from studies performed in other species.
Opioids are a diverse group of natural and synthetic drugs, which combine reversibly with specific receptors in the brain and spinal cord and modify the transmission and identification of pain. Among the 5 major classes of opioid receptors, [mu] and [kappa] receptors are most commonly targeted for analgesia. The distribution of opioid receptor types across vertebrate species is similar in the brainstem and spinal cord but differs in the forebrain. (1) Butorphanol tartrate (Torbugesic, Fort Dodge Animal Health, Fort Dodge, IA, USA) has been shown to act by binding [kappa] opioid receptors in the peripheral and central nervous systems and mimicking the activities of endogenous opioids. The drug also has minimal antagonist effects at [mu] opioid receptors. (2)
Previous studies have evaluated the analgesic effects of opioids, particularly those with [kappa] opioid receptor affinities, as well as their effects on anesthetic requirements in psittacine birds. (3-9) The analgesic efficacy of butorphanol has been studied in African grey parrots (Psittacus erithacus), blue-fronted Amazon parrots (Amazona aestiva), cockatoos (Cacatua species), and Hispaniolan Amazon parrots (Amazona ventralis). (3,4,6-9) Butorphanol administered at a dosage of 1 mg/kg intramuscular (IM) has been found to reduce the amount of inhaled isoflurane anesthetic necessary to maintain anesthesia in cockatoos and African grey parrots; however, this effect was not seen in blue-fronted Amazon parrots. (4) In a recent study in cockatoos, (9) butorphanol administered first at a loading dose of 3 mg/kg intravenous (IV) followed by a dosage of 0.75 mg/kg IV every 15 minutes administered as a constant rate infusion resulted in a significantly lower minimum anesthetic concentration of isoflurane compared with that in birds receiving saline controls. African grey parrots were found to have an increased threshold to an electric stimulus after butorphanol was administered at a dose of 2 mg/kg IMT; however, in another study, Hispaniolan Amazon parrots receiving the same dose of intramuscular butorphanol tartrate did not demonstrate a change in foot withdrawal at 30 minutes after drug administration. (8) Results of another study (10) stated that butorphanol dosed at 3 mg/kg IM had antinociceptive effects in Hispaniolan Amazon parrots. Furthermore, in a published study of Hispaniolan Amazon parrots, (8) plasma butorphanol concentrations (measured 1 hour after administration in each instance) analyzed after a butorphanol tartrate dose of 5 mg/kg IM were shown to be similar to those evaluated after a liposome-encapsulated butorphanol dose of 15 mg/kg SC, which had been shown to produce analgesia.
Despite the information available regarding the analgesic properties of butorphanol in psittacine birds, dosing intervals have not been established for any psittacine species. Published anecdotal dosing intervals for butorphanol range from every 2 to 4 to every 24 hours. (11,12) At the time of submission of this article, pharmacokinetic data for butorphanol in avian species was limited to a study in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). (13) Determination of plasma butorphanol concentrations after a dose of butorphanol that was shown to be analgesic in a psittacine species would provide a basis for recommendations on both interval dosing and continuous-rate infusions. The goals of this study in Hispaniolan Amazon parrots were to 1) evaluate the pharmacokinetics of butorphanol tartrate after IV, IM, and oral (PO) administration, and 2) determine the bioavailability of butorphanol tartrate after oral administration.
Materials and Methods
Twelve adult Hispaniolan Amazon parrots were used in the study, each approximately 8 years old and of undetermined sex. The mean (SD) body weight was 289 (17) g (range, 260-320 g). All birds were determined to be healthy based on physical examination and complete blood cell count results within reference range. The parrots were housed individually in suspended, wire cages in rooms maintained at 22[degrees]C (71.6[degrees]F) and were exposed to a 12-hour photoperiod. The birds were fed a pelleted diet (Exact Breeding Formula, Kaytee Products Inc, Chilton, WI, USA) and had unlimited access to water. The parrots had not received any drugs within 6 months before the study. This study was approved by the Louisiana State University Institutional Animal Care and Use Committee.
The study was set up in 3 parts to evaluate plasma butorphanol concentrations after IV, IM, and PO. A complete-crossover experimental design was used, with 3 months separating each part of the study. The birds were randomly assigned to 3 groups (n = 4) for each part. For the IV study, anesthesia was induced and maintained with isoflurane (delivered in oxygen at 1 L/min via facemask) administered at 5% and 2%, respectively, to facilitate administration of butorphanol tartrate 1% (5 mg/kg; Torbugesic) in the basilic vein. Each bird recovered subsequent to butorphanol administration. For the IM study, parrots were manually restrained for injection of butorphanol tartrate 1% (5 mg/kg) in the pectoral muscles. For the PO study, a 2 mg/mL butorphanol suspension was made by adding 10 mg butorphanol tartrate 1% to 4 mL sterile water. Each parrot was manually restrained during delivery of the suspension at a dose of 5 mg/kg via a metal feeding tube placed into the crop.
For each study, the 4 birds in each group were bled 3 times after dosing. Samples were collected at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes and 5, 15, 30, 60, 90, 120, 180, 240, and 300 minutes after butorphanol administration for both the IV and IM studies and for the PO study, respectively. Under manual restraint, a blood sample (0.6 mL) was collected from either the right or left jugular vein by 26-ga needle attached to a 3-mL plastic syringe precoated with heparin (1000 U/mL). The blood sample was transferred to 3-mL plain tubes, centrifuged (10 000g for 5 minutes) and kept at room temperature at 22[degrees]C (71.6[degrees]F) until the plasma was decanted within 2 hours of collection. The plasma was stored at -70[degrees]C (-94[degrees]F) for analysis approximately 2 weeks later.
Samples were prepared for analysis with a protein-precipitation method. Hispaniolan Amazon parrot plasma was aliquoted in 100-[micro]L volumes. Acetonitrile, at a volume of 300 [micro]L and containing 250 ppb of the internal standard (Levorphanol, Sigma-Aldrich, St Louis, MO, USA), was added to each sample tube and vortexed for 2 minutes. A standard curve of butorphanol tartrate (Cerilliant Corp, Round Rock, TX, USA), which bracketed the range of concentration, was prepared by spiking 100 [micro]L of blank parrot plasma. All samples, blanks, and standards were centrifuged for 10 minutes at 6000g. Supernatant was transferred and then dried under a nitrogen gas stream. To each tube of the supernatant, 150 [micro]L of 0.1% formic acid in water and 0.1% formic acid in methanol (50 : 50) was added, and a 0.45-[micro]m syringe filter was used to filter the resulting volume into a high-performance liquid chromatography vial for analysis. A triple-quadrupole mass spectrometer (Quattro II, Micromass, Danvers, MA, USA) was used for positive ion electrospray analysis. An 1100 high-performance liquid chromatography binary pump and an autosampler (Agilent, Palo Alto, CA, USA) were used to deliver 10 [micro]L of sample onto an Eclipse Plus [C.sub.18] column (3.0 x 100 mm, 3.5 [mu] particle size; Agilent). The mobile phases used were method A, 0.1% formic acid in water; and method B, 0.1% formic acid in methanol with a constant flow rate of 250 [micro]L/ min. The gradient was as follows: 0-1 minutes, 50% A: 50% B; at 5 minutes, 0% A: 100% B; at 7 minutes; 50% A:50% B until 12 minutes. Multiple reaction monitoring analysis was then performed. Ion transitions monitored were 258 > 133 m/z and 258 > 156.9 m/z for the internal standard and 328 > 309.9 m/z, 328 > 184.9 m/z, and 328 > 328 m/z for butorphanol. The dwell second time for each transition was 0.10 seconds, and the collision energy was 40 V for the internal standard and 45 V for butorphanol. The mass spectrometric conditions were optimized for butorphanol by infusion of pure standard. The limit of quantification and the limit of detection (3 x baseline noise) were 1.0 ng/mL and 0.1 ng/mL, respectively. The average intra-assay and interassay coefficient of variation was 11.8% and 12.4%, respectively. The recovery was 83%. The linearity of all curves had an average correlation coefficient of 0.9983.
Naive pooling of datum points (14) was used to generate a mean plasma butorphanol concentration at each time point. These mean concentrations were used for further pharmacokinetic calculations by computer program (WinNonlin Professional, version 5.2, Pharsight Corporation, Cary, NC, USA). Based on visual examination of the line fittings and Akaike's information criterion data, both the 1V and IM studies best fit a 1-compartment, open model with first-order absorption and elimination. Weighting of the data by use of the inverse square of the concentration improved the line fittings and the residual plots of data from both the IV and IM studies. Bioavailability was measured by the following equation:
%[F.sub.iv-im] = ([AUC.sub.im]/[AUC.sub.iv]) x 100,
where F is bioavailability, and AUC is the area under the plasma concentration versus time curve. Plasma concentrations for the PO study were low and erratic; therefore, pharmacokinetic analysis could not be performed. The A UC was calculated by measuring the partial A UC between each time point and adding those areas to obtain the total. Bioavailability was calculated with the following equation:
%[F.sub.iv-po] = ([AUC.sub.po]/[AUC.sub.iv]) x 100,
All birds were monitored during the study for signs of adverse effects, including apnea, sedation, excitation, vomiting, and diarrhea.
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Plasma concentration versus time curves and phannacokinetic parameters are presented in Figures 1 through 3 and Tables 1 and 2, respectively. Plasma butorphanol concentrations were undetectable in all birds at 6 hours, and at 4 hours, concentrations were undetectable in 2 of 4 birds (50%) and 1 of 4 birds (25%) after IV and IM administration, respectively. Mean plasma concentrations greater than 100 ng/mL were maintained for 1.5-2 hours and 2-3 hours after IV and IM administration, respectively. The calculated bioavailability of butorphanol administered IM and PO was 130% and 5.9%, respectively.
One parrot in the IV study developed apnea for a short period after butorphanol administration but recovered uneventfully from anesthesia. Significant adverse effects were not observed in any of the birds during the study.
Although plasma concentrations of butorphanol after IM administration have previously been reported in psittacine birds, pharmacokinetic data have not been published. To our knowledge, this is the first published study presenting the pharmacokinetic analysis of butorphanol tartrate in a psittacine species as well as the first study presenting pharmacokinetic analysis of butorphanol after oral administration in any avian species. The butorphanol dose of 5 mg/kg chosen for our study was based on previous studies of butorphanol in Hispaniolan Amazon parrots, including a recent study (8) on the serum concentrations and analgesic effects of liposome-encapsulated and standard butorphanol tartrate in parrots. In that study, (8) plasma concentrations of butorphanol and metabolites reported to provide analgesia were greater than 80 ng/mL. However, a direct relationship between plasma drug concentrations and analgesic effects could not be inferred from that study (8) because the assay measured butorphanol and its metabolites together, although some of the latter may not be effective. Results of our study showed that butorphanol tartrate administered to Hispaniolan Amazon parrots at a single dose of 5 mg/kg IM had high bioavailability and rapid elimination. In contrast, oral administration of the same dose of a butorphanol suspension resulted in low bioavailability (<10%), thus precluding the use of this route of administration for clinical purposes. Based on the results of our study, butorphanol tartrate administered to Hispaniolan Amazon parrots at a dose of 5 mg/kg IV or IM would have to be administered every 2 and 3 hours, respectively, to maintain plasma butorphanol concentrations likely to provide analgesia (>100 ng/mL). (8) It is possible that clinically useful analgesia occurs at lower plasma concentrations than those discussed here. In other species in which pharmacokinetic and pharmacodynamic studies have been evaluated, plasma butorphanol concentrations necessary to provide analgesia ranged from 1.7 ng/mL in humans (15) to 24.8 ng/mL in horses. (16) Therapeutic plasma concentrations vary with species and with the pain model being evaluated; therefore, caution should be used when evaluating plasma concentration alone to predict analgesia. Analgesia is likely determined by the concentration at the receptor, which lags behind plasma concentration. Furthermore, the affinity of the drug for the receptor may account for a longer duration of action than predicted by the termination half-life. (17) The termination half-life for butorphanol in Hispaniolan Amazon parrots calculated in the current study (0.49 hours and 0.51 hours for IV for IM administration, respectively) was shorter than that reported in red tailed-hawks (0.94 [+ or -] 0.30 h and 0.94 [+ or -] 0.26 h, IV and IM, respectively) and great horned owls (1.79 [+ or -] 1.36 h and 1.86 [+ or -] 1.56 h, IV and IM, respectively). (13)
The volume of distribution after IV and IM administration of butorphanol in this study was relatively large, suggesting a high degree of drug distribution to the tissues or, less likely, binding to plasma proteins. The relatively low bioavailability after PO administration may be attributed to a first-pass effect through the liver, where opioids are primarily metabolized by hydroxylation. (2)
The pharmacokinetic method approach used in this study was naive pooling of drug concentrations from multiple parrots, necessitated because the small size of the birds precluded blood collection from each parrot at all time points. A limitation of this method is that it does not allow measurement of variability in the calculated pharmacokinetic parameters because pooled concentrations are analyzed as though they were derived from a single bird. (14) However, strong interindividual variation in the absorption and duration of the effects of butorphanol has been documented in other species. (13,18,19)
Secondary effects noted during this study were seen in only 1 parrot (8%), which exhibited a short period of apnea after IV butorphanol administration. We attributed this effect to rapid administration of the drug. Sedation was not noted, and there were no other adverse effects observed during the study. Butorphanol dosed at 2 mg/kg IM did not cause any significant change in anesthetic and cardiopulmonary parameters in Hispaniolan Amazon parrots anesthetized with sevoflurane. (20) In red-tailed hawks and great horned owls injected with butorphanol at a dose of 0.5 mg/kg IV or IM, the subsequent decrease in heart or respiratory rate was not considered clinically relevant. (13) In the same study, (13) only minor sedative effects of short duration were noted in some birds. Secondary effects reported in dogs and cats after butorphanol administration include sedation, excitement, respiratory depression, ataxia, anorexia or diarrhea (rarely). These effects are considered transitory and are less severe than the effects seen with pure opioid agonists. (2)
Our results in Hispaniolan Amazon parrots show that butorphanol tartrate has high bioavailability and rapid elimination after IM administration in contrast to low bioavailability following PO administration. Based on these results, butorphanol tartrate used in Hispaniolan Amazon parrots at a dose of 5 mg/kg IV or IM should be administered every 2 and 3 hours, respectively, to maintain plasma concentrations consistent with published therapeutic levels. (8) Further studies (including multiple-dose studies) on the pharmacokinetics and pharmacodynamics of butorphanol use in other avian species are needed to provide more accurate dosage recommendations before broad clinical applications.
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David Sanchez-Migallon Guzman, LV, MS, Dipl ECZM (Avian), Dipl ACZM, Keven Flammer, DVM, Dipl ABVP (Avian), Joanne R. Paul-Murphy, DVM, Dipl ACZM, Steven A. Barker, MS, PhD, and Thomas N. Tully Jr, DVM, MS, Dipl ABVP (Avian), Dipl ECZM (Avian)
From the Departments of Veterinary Clinical Sciences (Guzman, Tully) and Comparative Biomedical Sciences (Barker), School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr, Baton Rouge, LA 70803-8410, USA; the Department of Medicine and Epidemiology, School of Veterinary Medicine, One Shields Ave, University of California, Davis, CA 95616, USA (Paul-Murphy); and the Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA (Flammer). Present address (Guzman): Department of Medicine and Epidemiology, School of Veterinary Medicine, One Shields Ave, University of California, Davis, CA 95616, USA.
Table 1. Mean pharmacokinetic parameters derived from naive, averaged data in a 1-compartment pharmacokinetic analysis after a single 5 mg/kg IV dose of butorphanol tartrate in 12 Hispaniolan Amazon parrots. Pharmacokinetic variable Value [C.sub.max] ng/mL 7.34 Elimination rate, 1/h 1.40 Termination half-life, 1/h 0.49 MRT h 0.71 AUC, h x ng/mL 523.01 AUMC, h x h x ng/mL 372.56 Cl, mL/h per kg 9.56 [V.sub.d(ss)], mL/kg 6.81 Abbreviations: [C.sub.max] indicates maximum concentration; MRT, mean residence time; AUC, area under the plasma concentration versus time curve; AUMC, area under the first moment curve; C1, clearance; [V.sub.d(ss)], volume of distribution at steady state. Table 2. Mean pharmacokinetic parameters derived from naive, averaged data in a 1-compartment pharmacokinetic analysis after a single 5 mg/kg IM dose of butorphanol tartrate in 12 Hispaniolan Amazon parrots. Pharmacokinetic variable Value [C.sub.max], ng/mL 653.42 [T.sub.max], h 0.25 Absorption rate, 1/h 8.97 Elimination rate, 1/h 1.35 Absorption half-life, 1/h 0.08 Termination half-life, 1/h 0.51 AUC, h x ng/mL 678.21 [V.sub.d], mL/kg 4.22 F 1.30 [V.sub.d(ss)], mL/kg 6.81 Abbreviations: [C.sub.max] indicates maximum concentration; [T.sub.max], time to maximum plasma concentration; AUC, area under the plasma concentration versus time curve; [V.sub.d], volume of distribution; F bioavailability; [V.sub.d(ss)], volume of distribution at steady state.
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|Author:||Guzman, David Sanchez-Migallon; Flammer, Keven; Paul-Murphy, Joanne R.; Barker, Steven A.; Tully, Th|
|Publication:||Journal of Avian Medicine and Surgery|
|Date:||Sep 1, 2011|
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