Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius) David Sanchez-Migallon Guzman, LV, MS; Butch KuKanich, DVM, PhD; Tracy L. Drazenovich, DVM; Glenn H. Olsen, DVM, PhD; Joanne R. Paul-Murphy, DVM
Objective—To determine the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in American kestrels (Falco sparverius). Animals—12 healthy adult American kestrels. Procedures—A single dose of hydromorphone (0.6 mg/kg) was administered IM (pectoral muscles) and IV (right jugular vein); the time between IM and IV administration experiments was 1 month. Blood samples were collected at 5 minutes, 1 hour, and 3 hours (n = 4 birds); 0.25, 1.5, and 9 hours (4); and 0.5, 2, and 6 hours (4) after drug administration. Plasma hydromorphone concentrations were determined by means of liquid chromatography with mass spectrometry, and pharmacokinetic parameters were calculated with a noncompartmental model. Mean plasma hydromorphone concentration for each time was determined with naïve averaged pharmacokinetic analysis. Results—Plasma hydromorphone concentrations were detectable in 2 and 3 birds at 6 hours after IM and IV administration, respectively, but not at 9 hours after administration. The fraction of the hydromorphone dose absorbed after IM administration was 0.75. The maximum observed plasma concentration was 112.1 ng/mL (5 minutes after administration). The terminal half-life was 1.25 and 1.26 hours after IV and IM administration, respectively. Conclusion and Clinical Relevance—Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated. (Am J Vet Res 2014;75:527–531)
O
pioids are a diverse group of drugs that bind to specific receptors in the brain, spinal cord, and peripheral tissues, modifying the transmission and perception of noxious stimuli in all vertebrate species tested. Opioid drugs are used for their analgesic properties, acting on the µ-, κ-, and δ-opioid receptors as well as the orphanin opioid-like receptor in the CNS and peripheral nervous system.1 The action of opioid drugs on these receptors activates G-proteins, leading to a reduction in transmission of nerve impulses and inhibition of Received September 8, 2013. Accepted January 16, 2014. From the Veterinary Teaching Hospital (Sanchez-Migallon Guzman) and Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616 (Drazenovich, Paul-Murphy); the Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 (KuKanich); and the Patuxent Wildlife Research Center, US Geological Survey, 12100 Beech Forest Rd, Ste 4039, Laurel, MD 20708 (Olsen). Supported by the Morris Animal Foundation (grant No. D10ZO-305). Address correspondence to Dr. Sanchez-Migallon Guzman (guzman@ ucdavis.edu). AJVR, Vol 75, No. 6, June 2014
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Cmax MRT
ABBREVIATIONS
Maximum observed plasma concentration Mean residence time
neurotransmitter release.2 Few studies3–5 regarding the distribution, quantity, and function of each opioid receptor type in birds have been reported. Hydromorphone is a µ-opioid receptor agonist with a potency approximately 5 to 7 times that of morphine in humans6 and analgesic efficacy and duration of action similar to oxymorphone in dogs and cats.7 Hydromorphone is administered by parenteral, transmucosal, and epidural routes to humans for the management of acute and chronic pain.8,9 That drug is metabolized in the liver, primarily by glucuronidation in most species, and the metabolite is excreted by the kidneys.10 Cost and availability have made hydromorphone an accepted alternative to oxymorphone for treatment of dogs and cats in North America.11 In addition, hydromorphone is an accepted alterna527
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tive to morphine because it does not cause histamine release after IV administration.12,13 Recent studies have provided additional information indicating the potential analgesic effects of opioid drugs in raptors. Hydromorphone hydrochloride has a doseresponsive (0.1, 0.3, and 0.6 mg/kg) thermal antinociceptive effect after IM administration to kestrels, suggesting that the drug has analgesic properties in this species.14 In contrast, butorphanol tartrate, a κ-opioid receptor agonist and µ-opioid receptor antagonist, does not have a significant thermal antinociceptive effect after IM administration to kestrels at doses of 1, 3, and 6 mg/kg.15 Tramadol hydrochloride significantly increases the foot withdrawal threshold temperature for kestrels after administration of a dose of 5 mg/kg, PO; however, higher doses (15 and 30 mg/kg) result in lower antinociceptive effects.16 Other studies have been conducted to determine the pharmacokinetics of opioid drugs in raptors. The pharmacokinetics of butorphanol has been determined for American kestrels (Falco sparverius),15 red-tailed hawks (Buteo jamaicensis), and great horned owls (Bubo virginianus),17 and the pharmacokinetics of fentanyl has been determined for red-tailed hawks.18 The pharmacokinetics of tramadol hydrochloride has been determined for bald eagles (Haliaeetus leucocephalus)19 and red-tailed hawks.20 To our knowledge, the pharmacokinetics of hydromorphone hydrochloride has not been determined for any species of bird. The objective of the study reported here was to determine the pharmacokinetics of hydromorphone hydrochloride after IM and IV administration of a single dose to American kestrels. Materials and Methods Animals—Twelve 2-year-old American kestrels (6 females and 6 males) were used in the study. The mean ± SD weight of the birds was 115 ± 6.2 g (median, 115.1 g; range, 105.6 to 126.4 g). All kestrels originated from the US Geological Survey Patuxent Wildlife Research Center in Maryland, were shipped to the University of California-Davis 18 months prior to the start of the study, and were determined to be healthy on the basis of physical examinations performed prior to and during the study. Kestrels were maintained in small social groups in three 8 X 10.3-foot rooms, with perches spaced throughout each room. They were maintained on a 12-hour light-dark cycle and fed thawed, previously frozen, medium-sized mice and provided water ad libitum. The experimental protocol was approved by the Institutional Animal Care and Use Committee of the University of California-Davis. Experimental design—The kestrels were assigned by means of a randomization procedure to 3 groups of 4 birds each; each group had predetermined blood sample collection times. At the start of the experimental period (0 minutes), each kestrel was manually restrained and received hydromorphone hydrochloridea (0.6 mg/kg, IM) in the left pectoral muscle. Birds were manually restrained for collection of blood samples (0.3 mL) from the jugular veins or medial metatarsal veins at the following predetermined times after drug administration: 5 minutes, 1 hour, and 3 hours (n = 4 kestrels); 0.25, 1.5, and 9 hours (4); and 0.5, 2, and 6 hours (4). The 528
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birds were kept in carriers throughout the blood sample collection period without access to food or water. Blood samples were collected into tubes containing heparin lithium and placed in ice-packed containers. Within 1 hour after collection, blood samples were centrifuged at 3,500 X g for 6 minutes. Plasma was collected and stored at –80°C until analysis. Another experiment was performed 1 month later. During the second experiment, birds were assigned to the same blood sample collection groups. Kestrels were manually restrained and received 0.6 mg of hydromorphone hydrochloride IV in the right jugular vein. Blood sample collection and processing was performed with the same procedures used during the first experiment. Measurement of plasma hydromorphone concentrations—Hydromorphone plasma concentrations were determined by means of liquid chromatographyb with mass spectrometry.c The qualifying ion for hydromorphoned had an m/z of 286.077, and the quantifying ion had an m/z of 185.091 (m/z, 286.077→185.091). The qualifying ion for the internal standard (hydromorphone-D6d) had an m/z of 292.193, and the quantifying ion had an m/z of 185.132 (m/z, 292.193→185.132). The mobile phase consisted of acetonitrile and a 0.1% formic acid solution at a flow rate of 0.3 mL/min. The mobile phase consisted of 98% acetonitrile from 0 to 1 minute with a linear gradient to 75% formic acid solution at 5 minutes, followed by a linear gradient to 98% formic acid solution at 6 minutes, with a total run time of 8 minutes. Separation was achieved with a 2.1 X 50-mm, 5-µm columne heated to 40°C. The internal standard solution (500 µL, containing hydromorphone-D6 [5 ng/ mL] in 2% ammonium hydroxide in water) was added to 0.05 mL of plasma. Solid phase extraction cartridgesf were conditioned with methanol (1 mL) followed by 2% ammonium hydroxide in water (1 mL); then, the plasma sample or standard was loaded (total volume, 0.6 mL), the solid phase extraction cartridgesf were rinsed with 2% ammonium hydroxide in 5% methanol (1 mL), and hydromorphone was eluted with methanol (1 mL). The eluate was evaporated until dry in a water bath (40°C) under a stream of air for 25 minutes and reconstituted with 200 µL of 2% acetonitrile in 0.1% formic acid. The injection volume was 50 µL. Owing to the low volume of pooled kestrel plasma samples, the standard curves were made with pooled canine plasma samples. The plasma standard curve was linear from 1 to 1,000 ng/mL and accepted if the predicted concentrations were within 15% above or below the actual concentration and the correlation coefficient was at least 0.99. The accuracy of the assay was determined with 3 replicates for each of the following hydromorphone concentrations: 2.5, 50, and 500 ng/mL in pooled kestrel plasma; results were compared with the standard curve determined with canine plasma samples. On the basis of the standard curve determined with canine plasma samples, the accuracy was 98% and the coefficient of variation was 7% for detection of hydromorphone in kestrel plasma samples. Pharmacokinetic analysis—Plasma sample hydromorphone concentrations were analyzed with a naïve AJVR, Vol 75, No. 6, June 2014
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blood samples/time, except times of 0.5, 2, and 6 hours after IM administration, for which the sample size was 3 because insufficient blood sample volumes were collected for determination of plasma hydromorphone concentrations). Uniform weighting of the hydromorphone plasma concentrations was used.g Results
Figure 1—Mean ± SD plasma concentration-time profiles after IM (black circles) and IV (white circles) administration of a single dose of hydromorphone (0.6 mg/kg) to 12 American kestrels (Falco sparverius). The time of hydromorphone administration was designated as 0 minutes. The continuous line represents the predicted values determined with compartmental parameters. Blood samples were collected at the following predetermined times following drug administration: 5 minutes, 1 hour, and 3 hours (n = 4 birds); 0.25, 1.5, and 9 hours (4; all results for 9 hours were below the lower limit of quantitation); and 0.5, 2, and 6 hours (4). Data were available for only 3 birds at 0.5, 2, and 6 hours after IM administration. Notice that the y-axis is logarithmic. Table 1—Pharmacokinetic parameters derived from naïve averaged data in a 2-compartment pharmacokinetic analysis after IV and IM administration of a single dose (0.6 mg/kg) of hydromorphone hydrochloride in 12 American kestrels (Falco sparverius). Pharmacokinetic parameter IV administration AUC0–∞ extrapolated (%) AUC0–∞ (h•ng/mL) AUClast (h•ng/mL) Plasma concentration extrapolated to 0 minutes (ng/mL) Plasma clearance (mL/min/kg) Terminal half-life (h) Terminal rate constant (h–1) MRT (h) Volume of distribution Steady-state method (L/kg) Area method (L/kg)
Estimate 1.90 141.80 139.02 166.10 62.32 1.25 0.554 1.14 4.26 6.75
IM administration AUC0–∞ extrapolated (%) 2.30 AUC0–∞ (h•ng/mL) 106.90 AUClast (h•ng/mL) 104.43 Plasma clearance corrected for bioavailability (mL/min/kg) 82.66 Cmax (ng/mL) 112.10 Terminal half-life (h) 1.26 Terminal rate constant (h–1) 0.548 MRT (h) 1.16 Time of Cmax (h) 0.083 Volume of distribution corrected for bioavailability (L/kg) 9.05 Mean absorption time (h) 0.03 Fraction of dose absorbed 0.75 AUC0–∞ = Area under the curve extrapolated to infinity. AUClast = Area under the curve up to the last measurable concentration.
averaged pharmacokinetic analysis by use of noncompartmental analysis.g The mean plasma concentration was calculated for each blood sample collection time (4 AJVR, Vol 75, No. 6, June 2014
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Plasma concentration-time curves and pharmacokinetic parameters of hydromorphone hydrochloride after IM and IV administration to American kestrels were summarized (Figure 1; Table 1). Hydromorphone was detected in plasma samples obtained from 2 and 3 birds at 6 hours after IM and IV administration, respectively; hydromorphone was not detected in any plasma sample obtained 9 hours after administration. For IM administration, the fraction of drug absorbed was 0.75. The Cmax was 112.1 ng/mL at 0.0833 hours (5 minutes), suggesting rapid absorption after IM administration. The terminal half-life was 1.25 and 1.26 hours after IV and IM administration, respectively.
Discussion To our knowledge, the study reported here is the first in which the pharmacokinetics of hydromorphone hydrochloride was determined for a species of bird. Hydromorphone hydrochloride administered at a dose of 0.6 mg/kg, IV or IM, rapidly attained Cmax (Cmax after IM administration, 112.1 ng/mL at 5 minutes) in American kestrels. Hydromorphone was well absorbed after IM administration as indicated by the high bioavailability. Plasma concentrations of hydromorphone decreased rapidly after IV and IM administration. The short half-life of hydromorphone following IM administration (1.26 hours), the rapid plasma clearance after IV administration (62.32 mL/min/kg; hepatic blood flow, approx 59 mL/min/kg21), and the large volume of distribution after IV administration as determined with the area method (6.75 L/kg) for the American kestrels were similar to values of those parameters for opioids in other species.22 Interestingly, the half-life after IM administration (1.25 hours) was slightly longer than the MRT (1.16 hours). This could have been attributable to elimination of most of the drug during the distribution phase, which would result in an MRT shorter than the terminal half-life. This finding could also have been attributable to differences in the methods of calculation; the MRT was determined by dividing the area under the first moment time curve by the area under the concentration-time curve, but the terminal half-life was determined on the basis of log linear regression of the last 3 data values. The dose of hydromorphone (0.6 mg/kg) used in the present study was the highest effective dose determined in another study14 conducted by personnel in 529
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our laboratory to evaluate the antinociceptive effects of hydromorphone hydrochloride in American kestrels. The low doses of hydromorphone evaluated in that other study14 (0.3 and 0.1 mg/kg) also had thermal antinociceptive effects. Dose-dependent pharmacokinetics of hydromorphone has been reported for dogs23; that drug could have similar pharmacokinetics in American kestrels. Thus, extrapolation of the findings of the present study for lower or higher doses during clinical use (eg, determination of low-dose continuousrate infusions) should be performed cautiously. On the basis of results of the present study, a hydromorphone continuous-rate infusion of 0.015 mg/kg/h would result in a steady-state plasma concentration of 4 ng/mL, 0.03 mg/kg/h would result in a steady-state plasma concentration of 8 ng/mL, and 0.037 mg/kg/h would result in a steady-state plasma of 10 ng/mL, if the plasma clearance remains constant. These values were calculated with the following equation: rate = clearance X concentration at steady state. The minimum effective concentration of hydromorphone in kestrels is not known, but the pharmacokinetics and antinociceptive effects of various infusion rates of hydromorphone could be evaluated in future studies to determine minimum infusion rates and plasma concentrations associated with antinociception. Administration of 0.6 mg of hydromorphone/kg yielded plasma concentrations > 1 ng/mL for 6 hours in 2 and 3 kestrels after IM and IV administration, respectively, with data for that time in the present study. Thermal antinociceptive effects were detected 3 to 6 hours after administration of that dose of hydromorphone in kestrels in another study.14 Plasma concentrations of hydromorphone of 2 to 3 ng/mL are anticipated to have antinociceptive effects in dogs22; in humans, analgesic effects of hydromorphone are variably related to plasma concentrations of 0.5 to 4.5 ng/mL.24 However, a direct relationship between plasma drug concentrations and antinociceptive effects cannot be inferred, and caution should be used when predicting analgesia on the basis of plasma concentration alone. Antinociceptive effects of opioids are likely determined by concentrations at receptors, which lag behind plasma concentrations.25 Also, the affinity of a drug for receptors, the quantity and distribution of receptors, and the interactions with other receptors might also determine the antinociceptive effect. Furthermore, the presence of active metabolites of hydromorphone was not determined in the present study and might vary among species. Liquid chromatography–tandem mass spectrometry analysis results for urine and plasma samples obtained from rats26 and urine samples obtained from humans27 treated with hydromorphone indicate dihydromorphine, dihydroisomorphine, and the 3-glucuronide of hydromorphone and its 6-hydroxy metabolites can be identified in these species, with the 3-glucuronide present in the highest concentrations. Domestic cats have a significantly lower capacity to glucuronidate exogenous drugs and a different metabolite profile, compared with most other mammalian species.28 Hydromorphone metabolite concentrations may be different in American kestrels versus other species. The pharmacokinetic method used in the present study was naïve averaged pooling of drug concentra530
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tions determined for multiple birds; this was necessary because the small size of the birds precluded collection of blood samples from each kestrel at all times. A limitation of this method was that it did not allow measurement of variability in the calculated pharmacokinetic parameters because pooled concentrations were analyzed as though they were determined for a single bird.29 However, high interindividual variation in the pharmacokinetics and duration of the effects of hydromorphone has been determined for other species.13,22,23 Adverse effects of administration of hydromorphone at a dose of 0.6 mg/kg include moderate to severe sedation in some American kestrels.14 In dogs, reported adverse effects of hydromorphone include signs of nausea, vomiting, defecation, panting, vocalization, sedation, CNS depression, bradycardia, and decreased gastrointestinal tract motility after chronic use.10 Adverse effects of hydromorphone in cats include signs of nausea, ataxia, hyperesthesia, hyperthermia, and behavioral changes without concomitant tranquilization.10 Hydromorphone should be administered with caution to American kestrels and other species of birds until further studies have been conducted to evaluate cardiorespiratory and thermoregulatory effects and more clinical information is available for such animals. Results of the present study indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies would be needed to determine effects of other doses, other administration routes, constant rate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels and other avian species. Results of such studies may allow determination of further recommendations regarding administration of hydromorphone to such animals. a. b. c. d. e. f. g.
Hospira Inc, Lake Forest, Ill. Shimadzu Prominence, Shimadzu Scientific Instruments, Columbia, Md. API 3000, Applied Biosystems, Foster City, Calif. Cerilliant, Round Rock, Tex. Ace C18, MAC-MOD Analytical, Chadds Ford, Pa. Strata C18, Phenomenex, Torrence, Calif. WinNonlin, version 5.2, Pharsight Corp, Mountain View, Calif.
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Lamont L, Mathews K. Opioids, nonsteroidal anti-inflammatories, and analgesic adjuvants. In: Tranquilli W, Thurmon J, Grimm K, eds. Lumb & Jones’ veterinary anesthesia. 4th ed. Ames, Iowa: Blackwell Publishing, 2007;241–272. Pan Z, Hirakawa N, Fields HL. A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin. Neuron 2000;26:515–522. Reiner A, Brauth SE, Kitt CA, et al. Distribution of mu, delta, and kappa opiate receptor types in the forebrain and midbrain of pigeons. J Comp Neurol 1989;280:359–382. Csillag A, Bourne RC, Stewart MG. Distribution of mu, delta, and kappa opioid receptor binding sites in the brain of the one-day-old domestic chick (Gallus domesticus): an in vitro quantitative autoradiographic study. J Comp Neurol 1990;302:543–551. Khurshid N, Agarwal V, Iyengar S. Expression of mu- and deltaopioid receptors in song control regions of adult male zebra AJVR, Vol 75, No. 6, June 2014
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finches (Taenopygia guttata). J Chem Neuroanat 2009;37:158– 169. Dunbar PJ, Chapman CR, Buckley FP, et al. Clinical analgesic equivalence for morphine and hydromorphone with prolonged PCA. Pain 1996;68:265–270. Bateman SW, Haldane S, Stephens JA. Comparison of the analgesic efficacy of hydromorphone and oxymorphone in dogs and cats: a randomized blinded study. Vet Anaesth Analg 2008;35:341–347. Reidenberg MM, Goodman H, Erle H, et al. Hydromorphone levels and pain control in patients with severe chronic pain. Clin Pharmacol Ther 1988;44:376–382. Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. J Pain Symptom Manage 2003;25:169– 178. Plumb D. Hydromorphone. In: Plumb D, ed. Veterinary drug handbook. 7th ed. Stockholm, Wis: PharmaVet Inc, 2011;509– 511. Pettifer G, Dyson D. Hydromorphone: a cost-effective alternative to the use of oxymorphone. Can Vet J 2000;41:135–137. Smith LJ, Yu JK, Bjorling DE, et al. Effects of hydromorphone or oxymorphone, with or without acepromazine, on preanesthetic sedation, physiologic values, and histamine release in dogs. J Am Vet Med Assoc 2001;218:1101–1105. Wegner K, Robertson SA, Kollias-Baker C, et al. Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats. J Vet Pharmacol Ther 2004;27:329–336. Guzman DS, Drazenovich TL, Olsen GH, et al. Evaluation of thermal antinociceptive effects after intramuscular administration of hydromorphone hydrochloride to American kestrels (Falco sparverius). Am J Vet Res 2013;74:817–822. Guzman DS, Drazenovich TL, Kukanich B, et al. Evaluation of the thermal antinociceptive effects and pharmacokinetics after intramuscular administration of butorphanol tartrate to American kestrels (Falco sparverius). Am J Vet Res 2014;75:11–18. Guzman DS, Drazenovich TL, Olsen G, et al. Evaluation of the thermal antinociceptive effects after oral administration of tramadol hydrochloride to American kestrels (Falco sparverius). Am J Vet Res 2014;in press. Riggs SM, Hawkins MG, Craigmill AL, et al. Pharmacokinetics of butorphanol tartrate in red-tailed hawks (Buteo jamai-
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censis) and great horned owls (Bubo virginianus). Am J Vet Res 2008;69:596–603. Pavez JC, Hawkins MG, Pascoe PJ, et al. Effect of fentanyl target-controlled infusions on isoflurane minimum anaesthetic concentration and cardiovascular function in red-tailed hawks (Buteo jamaicensis). Vet Anaesth Analg 2011;38:344351. Souza MJ, Martin-Jimenez T, Jones MP, et al. Pharmacokinetics of intravenous and oral tramadol in the bald eagle (Haliaeetus leucocephalus). J Avian Med Surg 2009;23:247–252. Souza MJ, Martin-Jimenez T, Jones MP, et al. Pharmacokinetics of oral tramadol in red-tailed hawks (Buteo jamaicensis). J Vet Pharmacol Ther 2011;34:86–88. Nichols JW, Bennett RS, Rossmann R, et al. A physiologically based toxicokinetic model for methylmercury in female American kestrels. Environ Toxicol Chem 2010;29:1854–1867. Guedes AG, Papich MG, Rude EP, et al. Pharmacokinetics and physiological effects of intravenous hydromorphone in conscious dogs. J Vet Pharmacol Ther 2008;31:334–343. KuKanich B, Hogan BK, Krugner-Higby LA, et al. Pharmacokinetics of hydromorphone hydrochloride in healthy dogs. Vet Anaesth Analg 2008;35:256–264. Coda B, Tanaka A, Jacobson RC, et al. Hydromorphone analgesia after intravenous bolus administration. Pain 1997;71:41–48. Bailey PL, Egan TD, Stanley TH. Intravenous opioid anesthetics. In: Miller RD, ed. Anesthesia. Philadelphia: Churchill Livingstone, 2000;273–376. Zheng M, McErlane KM, Ong MC. Hydromorphone metabolites: isolation and identification from pooled urine samples of a cancer patient. Xenobiotica 2002;32:427–439. Zheng M, McErlane KM, Ong MC. LC-MS-MS analysis of hydromorphone and hydromorphone metabolites with application to a pharmacokinetic study in the male Sprague-Dawley rat. Xenobiotica 2002;32:141–151. Court MH, Greenblatt DJ. Molecular basis for deficient acetaminophen glucuronidation in cats. An interspecies comparison of enzyme kinetics in liver microsomes. Biochem Pharmacol 1997;53:1041–1047. Gibaldi M, Perrier D. Noncompartmental analysis based on statistical moment. In: Pharmacokinetics. New York: Marcel Dekker Inc, 1982;409–417.
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Objective—To determine the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in American kestrels (Falco sparverius). Animals—12 healthy adult American kestrels. Procedures—A single dose of hydromorphone (0.6 mg/kg) was administered IM (pectoral muscles) and IV (right jugular vein); the time between IM and IV administration experiments was 1 month. Blood samples were collected at 5 minutes, 1 hour, and 3 hours (n = 4 birds); 0.25, 1.5, and 9 hours (4); and 0.5, 2, and 6 hours (4) after drug administration. Plasma hydromorphone concentrations were determined by means of liquid chromatography with mass spectrometry, and pharmacokinetic parameters were calculated with a noncompartmental model. Mean plasma hydromorphone concentration for each time was determined with naïve averaged pharmacokinetic analysis. Results—Plasma hydromorphone concentrations were detectable in 2 and 3 birds at 6 hours after IM and IV administration, respectively, but not at 9 hours after administration. The fraction of the hydromorphone dose absorbed after IM administration was 0.75. The maximum observed plasma concentration was 112.1 ng/mL (5 minutes after administration). The terminal half-life was 1.25 and 1.26 hours after IV and IM administration, respectively. Conclusion and Clinical Relevance—Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated. (Am J Vet Res 2014;75:527–531)
O
pioids are a diverse group of drugs that bind to specific receptors in the brain, spinal cord, and peripheral tissues, modifying the transmission and perception of noxious stimuli in all vertebrate species tested. Opioid drugs are used for their analgesic properties, acting on the µ-, κ-, and δ-opioid receptors as well as the orphanin opioid-like receptor in the CNS and peripheral nervous system.1 The action of opioid drugs on these receptors activates G-proteins, leading to a reduction in transmission of nerve impulses and inhibition of Received September 8, 2013. Accepted January 16, 2014. From the Veterinary Teaching Hospital (Sanchez-Migallon Guzman) and Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616 (Drazenovich, Paul-Murphy); the Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 (KuKanich); and the Patuxent Wildlife Research Center, US Geological Survey, 12100 Beech Forest Rd, Ste 4039, Laurel, MD 20708 (Olsen). Supported by the Morris Animal Foundation (grant No. D10ZO-305). Address correspondence to Dr. Sanchez-Migallon Guzman (guzman@ ucdavis.edu). AJVR, Vol 75, No. 6, June 2014
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Cmax MRT
ABBREVIATIONS
Maximum observed plasma concentration Mean residence time
neurotransmitter release.2 Few studies3–5 regarding the distribution, quantity, and function of each opioid receptor type in birds have been reported. Hydromorphone is a µ-opioid receptor agonist with a potency approximately 5 to 7 times that of morphine in humans6 and analgesic efficacy and duration of action similar to oxymorphone in dogs and cats.7 Hydromorphone is administered by parenteral, transmucosal, and epidural routes to humans for the management of acute and chronic pain.8,9 That drug is metabolized in the liver, primarily by glucuronidation in most species, and the metabolite is excreted by the kidneys.10 Cost and availability have made hydromorphone an accepted alternative to oxymorphone for treatment of dogs and cats in North America.11 In addition, hydromorphone is an accepted alterna527
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tive to morphine because it does not cause histamine release after IV administration.12,13 Recent studies have provided additional information indicating the potential analgesic effects of opioid drugs in raptors. Hydromorphone hydrochloride has a doseresponsive (0.1, 0.3, and 0.6 mg/kg) thermal antinociceptive effect after IM administration to kestrels, suggesting that the drug has analgesic properties in this species.14 In contrast, butorphanol tartrate, a κ-opioid receptor agonist and µ-opioid receptor antagonist, does not have a significant thermal antinociceptive effect after IM administration to kestrels at doses of 1, 3, and 6 mg/kg.15 Tramadol hydrochloride significantly increases the foot withdrawal threshold temperature for kestrels after administration of a dose of 5 mg/kg, PO; however, higher doses (15 and 30 mg/kg) result in lower antinociceptive effects.16 Other studies have been conducted to determine the pharmacokinetics of opioid drugs in raptors. The pharmacokinetics of butorphanol has been determined for American kestrels (Falco sparverius),15 red-tailed hawks (Buteo jamaicensis), and great horned owls (Bubo virginianus),17 and the pharmacokinetics of fentanyl has been determined for red-tailed hawks.18 The pharmacokinetics of tramadol hydrochloride has been determined for bald eagles (Haliaeetus leucocephalus)19 and red-tailed hawks.20 To our knowledge, the pharmacokinetics of hydromorphone hydrochloride has not been determined for any species of bird. The objective of the study reported here was to determine the pharmacokinetics of hydromorphone hydrochloride after IM and IV administration of a single dose to American kestrels. Materials and Methods Animals—Twelve 2-year-old American kestrels (6 females and 6 males) were used in the study. The mean ± SD weight of the birds was 115 ± 6.2 g (median, 115.1 g; range, 105.6 to 126.4 g). All kestrels originated from the US Geological Survey Patuxent Wildlife Research Center in Maryland, were shipped to the University of California-Davis 18 months prior to the start of the study, and were determined to be healthy on the basis of physical examinations performed prior to and during the study. Kestrels were maintained in small social groups in three 8 X 10.3-foot rooms, with perches spaced throughout each room. They were maintained on a 12-hour light-dark cycle and fed thawed, previously frozen, medium-sized mice and provided water ad libitum. The experimental protocol was approved by the Institutional Animal Care and Use Committee of the University of California-Davis. Experimental design—The kestrels were assigned by means of a randomization procedure to 3 groups of 4 birds each; each group had predetermined blood sample collection times. At the start of the experimental period (0 minutes), each kestrel was manually restrained and received hydromorphone hydrochloridea (0.6 mg/kg, IM) in the left pectoral muscle. Birds were manually restrained for collection of blood samples (0.3 mL) from the jugular veins or medial metatarsal veins at the following predetermined times after drug administration: 5 minutes, 1 hour, and 3 hours (n = 4 kestrels); 0.25, 1.5, and 9 hours (4); and 0.5, 2, and 6 hours (4). The 528
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birds were kept in carriers throughout the blood sample collection period without access to food or water. Blood samples were collected into tubes containing heparin lithium and placed in ice-packed containers. Within 1 hour after collection, blood samples were centrifuged at 3,500 X g for 6 minutes. Plasma was collected and stored at –80°C until analysis. Another experiment was performed 1 month later. During the second experiment, birds were assigned to the same blood sample collection groups. Kestrels were manually restrained and received 0.6 mg of hydromorphone hydrochloride IV in the right jugular vein. Blood sample collection and processing was performed with the same procedures used during the first experiment. Measurement of plasma hydromorphone concentrations—Hydromorphone plasma concentrations were determined by means of liquid chromatographyb with mass spectrometry.c The qualifying ion for hydromorphoned had an m/z of 286.077, and the quantifying ion had an m/z of 185.091 (m/z, 286.077→185.091). The qualifying ion for the internal standard (hydromorphone-D6d) had an m/z of 292.193, and the quantifying ion had an m/z of 185.132 (m/z, 292.193→185.132). The mobile phase consisted of acetonitrile and a 0.1% formic acid solution at a flow rate of 0.3 mL/min. The mobile phase consisted of 98% acetonitrile from 0 to 1 minute with a linear gradient to 75% formic acid solution at 5 minutes, followed by a linear gradient to 98% formic acid solution at 6 minutes, with a total run time of 8 minutes. Separation was achieved with a 2.1 X 50-mm, 5-µm columne heated to 40°C. The internal standard solution (500 µL, containing hydromorphone-D6 [5 ng/ mL] in 2% ammonium hydroxide in water) was added to 0.05 mL of plasma. Solid phase extraction cartridgesf were conditioned with methanol (1 mL) followed by 2% ammonium hydroxide in water (1 mL); then, the plasma sample or standard was loaded (total volume, 0.6 mL), the solid phase extraction cartridgesf were rinsed with 2% ammonium hydroxide in 5% methanol (1 mL), and hydromorphone was eluted with methanol (1 mL). The eluate was evaporated until dry in a water bath (40°C) under a stream of air for 25 minutes and reconstituted with 200 µL of 2% acetonitrile in 0.1% formic acid. The injection volume was 50 µL. Owing to the low volume of pooled kestrel plasma samples, the standard curves were made with pooled canine plasma samples. The plasma standard curve was linear from 1 to 1,000 ng/mL and accepted if the predicted concentrations were within 15% above or below the actual concentration and the correlation coefficient was at least 0.99. The accuracy of the assay was determined with 3 replicates for each of the following hydromorphone concentrations: 2.5, 50, and 500 ng/mL in pooled kestrel plasma; results were compared with the standard curve determined with canine plasma samples. On the basis of the standard curve determined with canine plasma samples, the accuracy was 98% and the coefficient of variation was 7% for detection of hydromorphone in kestrel plasma samples. Pharmacokinetic analysis—Plasma sample hydromorphone concentrations were analyzed with a naïve AJVR, Vol 75, No. 6, June 2014
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blood samples/time, except times of 0.5, 2, and 6 hours after IM administration, for which the sample size was 3 because insufficient blood sample volumes were collected for determination of plasma hydromorphone concentrations). Uniform weighting of the hydromorphone plasma concentrations was used.g Results
Figure 1—Mean ± SD plasma concentration-time profiles after IM (black circles) and IV (white circles) administration of a single dose of hydromorphone (0.6 mg/kg) to 12 American kestrels (Falco sparverius). The time of hydromorphone administration was designated as 0 minutes. The continuous line represents the predicted values determined with compartmental parameters. Blood samples were collected at the following predetermined times following drug administration: 5 minutes, 1 hour, and 3 hours (n = 4 birds); 0.25, 1.5, and 9 hours (4; all results for 9 hours were below the lower limit of quantitation); and 0.5, 2, and 6 hours (4). Data were available for only 3 birds at 0.5, 2, and 6 hours after IM administration. Notice that the y-axis is logarithmic. Table 1—Pharmacokinetic parameters derived from naïve averaged data in a 2-compartment pharmacokinetic analysis after IV and IM administration of a single dose (0.6 mg/kg) of hydromorphone hydrochloride in 12 American kestrels (Falco sparverius). Pharmacokinetic parameter IV administration AUC0–∞ extrapolated (%) AUC0–∞ (h•ng/mL) AUClast (h•ng/mL) Plasma concentration extrapolated to 0 minutes (ng/mL) Plasma clearance (mL/min/kg) Terminal half-life (h) Terminal rate constant (h–1) MRT (h) Volume of distribution Steady-state method (L/kg) Area method (L/kg)
Estimate 1.90 141.80 139.02 166.10 62.32 1.25 0.554 1.14 4.26 6.75
IM administration AUC0–∞ extrapolated (%) 2.30 AUC0–∞ (h•ng/mL) 106.90 AUClast (h•ng/mL) 104.43 Plasma clearance corrected for bioavailability (mL/min/kg) 82.66 Cmax (ng/mL) 112.10 Terminal half-life (h) 1.26 Terminal rate constant (h–1) 0.548 MRT (h) 1.16 Time of Cmax (h) 0.083 Volume of distribution corrected for bioavailability (L/kg) 9.05 Mean absorption time (h) 0.03 Fraction of dose absorbed 0.75 AUC0–∞ = Area under the curve extrapolated to infinity. AUClast = Area under the curve up to the last measurable concentration.
averaged pharmacokinetic analysis by use of noncompartmental analysis.g The mean plasma concentration was calculated for each blood sample collection time (4 AJVR, Vol 75, No. 6, June 2014
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Plasma concentration-time curves and pharmacokinetic parameters of hydromorphone hydrochloride after IM and IV administration to American kestrels were summarized (Figure 1; Table 1). Hydromorphone was detected in plasma samples obtained from 2 and 3 birds at 6 hours after IM and IV administration, respectively; hydromorphone was not detected in any plasma sample obtained 9 hours after administration. For IM administration, the fraction of drug absorbed was 0.75. The Cmax was 112.1 ng/mL at 0.0833 hours (5 minutes), suggesting rapid absorption after IM administration. The terminal half-life was 1.25 and 1.26 hours after IV and IM administration, respectively.
Discussion To our knowledge, the study reported here is the first in which the pharmacokinetics of hydromorphone hydrochloride was determined for a species of bird. Hydromorphone hydrochloride administered at a dose of 0.6 mg/kg, IV or IM, rapidly attained Cmax (Cmax after IM administration, 112.1 ng/mL at 5 minutes) in American kestrels. Hydromorphone was well absorbed after IM administration as indicated by the high bioavailability. Plasma concentrations of hydromorphone decreased rapidly after IV and IM administration. The short half-life of hydromorphone following IM administration (1.26 hours), the rapid plasma clearance after IV administration (62.32 mL/min/kg; hepatic blood flow, approx 59 mL/min/kg21), and the large volume of distribution after IV administration as determined with the area method (6.75 L/kg) for the American kestrels were similar to values of those parameters for opioids in other species.22 Interestingly, the half-life after IM administration (1.25 hours) was slightly longer than the MRT (1.16 hours). This could have been attributable to elimination of most of the drug during the distribution phase, which would result in an MRT shorter than the terminal half-life. This finding could also have been attributable to differences in the methods of calculation; the MRT was determined by dividing the area under the first moment time curve by the area under the concentration-time curve, but the terminal half-life was determined on the basis of log linear regression of the last 3 data values. The dose of hydromorphone (0.6 mg/kg) used in the present study was the highest effective dose determined in another study14 conducted by personnel in 529
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our laboratory to evaluate the antinociceptive effects of hydromorphone hydrochloride in American kestrels. The low doses of hydromorphone evaluated in that other study14 (0.3 and 0.1 mg/kg) also had thermal antinociceptive effects. Dose-dependent pharmacokinetics of hydromorphone has been reported for dogs23; that drug could have similar pharmacokinetics in American kestrels. Thus, extrapolation of the findings of the present study for lower or higher doses during clinical use (eg, determination of low-dose continuousrate infusions) should be performed cautiously. On the basis of results of the present study, a hydromorphone continuous-rate infusion of 0.015 mg/kg/h would result in a steady-state plasma concentration of 4 ng/mL, 0.03 mg/kg/h would result in a steady-state plasma concentration of 8 ng/mL, and 0.037 mg/kg/h would result in a steady-state plasma of 10 ng/mL, if the plasma clearance remains constant. These values were calculated with the following equation: rate = clearance X concentration at steady state. The minimum effective concentration of hydromorphone in kestrels is not known, but the pharmacokinetics and antinociceptive effects of various infusion rates of hydromorphone could be evaluated in future studies to determine minimum infusion rates and plasma concentrations associated with antinociception. Administration of 0.6 mg of hydromorphone/kg yielded plasma concentrations > 1 ng/mL for 6 hours in 2 and 3 kestrels after IM and IV administration, respectively, with data for that time in the present study. Thermal antinociceptive effects were detected 3 to 6 hours after administration of that dose of hydromorphone in kestrels in another study.14 Plasma concentrations of hydromorphone of 2 to 3 ng/mL are anticipated to have antinociceptive effects in dogs22; in humans, analgesic effects of hydromorphone are variably related to plasma concentrations of 0.5 to 4.5 ng/mL.24 However, a direct relationship between plasma drug concentrations and antinociceptive effects cannot be inferred, and caution should be used when predicting analgesia on the basis of plasma concentration alone. Antinociceptive effects of opioids are likely determined by concentrations at receptors, which lag behind plasma concentrations.25 Also, the affinity of a drug for receptors, the quantity and distribution of receptors, and the interactions with other receptors might also determine the antinociceptive effect. Furthermore, the presence of active metabolites of hydromorphone was not determined in the present study and might vary among species. Liquid chromatography–tandem mass spectrometry analysis results for urine and plasma samples obtained from rats26 and urine samples obtained from humans27 treated with hydromorphone indicate dihydromorphine, dihydroisomorphine, and the 3-glucuronide of hydromorphone and its 6-hydroxy metabolites can be identified in these species, with the 3-glucuronide present in the highest concentrations. Domestic cats have a significantly lower capacity to glucuronidate exogenous drugs and a different metabolite profile, compared with most other mammalian species.28 Hydromorphone metabolite concentrations may be different in American kestrels versus other species. The pharmacokinetic method used in the present study was naïve averaged pooling of drug concentra530
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tions determined for multiple birds; this was necessary because the small size of the birds precluded collection of blood samples from each kestrel at all times. A limitation of this method was that it did not allow measurement of variability in the calculated pharmacokinetic parameters because pooled concentrations were analyzed as though they were determined for a single bird.29 However, high interindividual variation in the pharmacokinetics and duration of the effects of hydromorphone has been determined for other species.13,22,23 Adverse effects of administration of hydromorphone at a dose of 0.6 mg/kg include moderate to severe sedation in some American kestrels.14 In dogs, reported adverse effects of hydromorphone include signs of nausea, vomiting, defecation, panting, vocalization, sedation, CNS depression, bradycardia, and decreased gastrointestinal tract motility after chronic use.10 Adverse effects of hydromorphone in cats include signs of nausea, ataxia, hyperesthesia, hyperthermia, and behavioral changes without concomitant tranquilization.10 Hydromorphone should be administered with caution to American kestrels and other species of birds until further studies have been conducted to evaluate cardiorespiratory and thermoregulatory effects and more clinical information is available for such animals. Results of the present study indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies would be needed to determine effects of other doses, other administration routes, constant rate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels and other avian species. Results of such studies may allow determination of further recommendations regarding administration of hydromorphone to such animals. a. b. c. d. e. f. g.
Hospira Inc, Lake Forest, Ill. Shimadzu Prominence, Shimadzu Scientific Instruments, Columbia, Md. API 3000, Applied Biosystems, Foster City, Calif. Cerilliant, Round Rock, Tex. Ace C18, MAC-MOD Analytical, Chadds Ford, Pa. Strata C18, Phenomenex, Torrence, Calif. WinNonlin, version 5.2, Pharsight Corp, Mountain View, Calif.
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