Pharmacokinetics of meloxicam after intravenous, intramuscular, and oral administration of a single dose to Hispaniolan Amazon parrots (Amazona ventralis)

Christine M. Molter Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.

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Michael H. Court Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, MA 02111.

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Gretchen A. Cole Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.

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David J. Gagnon Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.

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Suwagmani Hazarika Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, MA 02111.

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Joanne R. Paul-Murphy Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Abstract

Objective—To compare pharmacokinetics after IV, IM, and oral administration of a single dose of meloxicam to Hispaniolan Amazon parrots (Amazona ventralis).

Animals—11 healthy parrots.

Procedures—Cohorts of 8 of the 11 birds comprised 3 experimental groups for a crossover study. Pharmacokinetics were determined from plasma concentrations measured via high-performance liquid chromatography after IV, IM, and oral administration of meloxicam at a dose of 1 mg/kg.

Results—Initial mean ± SD plasma concentration of 17.3 ± 9.0 μg/mL was measured 5 minutes after IV administration, whereas peak mean concentration was 9.3 ± 1.8 μg/mL 15 minutes after IM administration. At 12 hours after administration, mean plasma concentrations for IV (3.7 ± 2.5 μg/mL) and IM (3.5 ± 2.2 μg/mL) administration were similar. Peak mean plasma concentration (3.5 ± 1.2 μg/mL) was detected 6 hours after oral administration. Absolute systemic bioavailability of meloxicam after IM administration was 100% but was lower after oral administration (range, 49% to 75%). Elimination half-lives after IV, IM, and oral administration were similar (15.9 ± 4.4 hours, 15.1 ± 7.7 hours, and 15.8 ± 8.6 hours, respectively).

Conclusions and Clinical Relevance—Pharmacokinetic data may provide useful information for use of meloxicam in Hispaniolan Amazon parrots. A mean plasma concentration of 3.5 μg/mL would be expected to provide analgesia in Hispaniolan Amazon parrots; however, individual variation may result in some birds having low plasma meloxicam concentrations after IV, IM, or oral administration. After oral administration, meloxicam concentration slowly reached the target plasma concentration, but that concentration was not sustained in most birds.

Abstract

Objective—To compare pharmacokinetics after IV, IM, and oral administration of a single dose of meloxicam to Hispaniolan Amazon parrots (Amazona ventralis).

Animals—11 healthy parrots.

Procedures—Cohorts of 8 of the 11 birds comprised 3 experimental groups for a crossover study. Pharmacokinetics were determined from plasma concentrations measured via high-performance liquid chromatography after IV, IM, and oral administration of meloxicam at a dose of 1 mg/kg.

Results—Initial mean ± SD plasma concentration of 17.3 ± 9.0 μg/mL was measured 5 minutes after IV administration, whereas peak mean concentration was 9.3 ± 1.8 μg/mL 15 minutes after IM administration. At 12 hours after administration, mean plasma concentrations for IV (3.7 ± 2.5 μg/mL) and IM (3.5 ± 2.2 μg/mL) administration were similar. Peak mean plasma concentration (3.5 ± 1.2 μg/mL) was detected 6 hours after oral administration. Absolute systemic bioavailability of meloxicam after IM administration was 100% but was lower after oral administration (range, 49% to 75%). Elimination half-lives after IV, IM, and oral administration were similar (15.9 ± 4.4 hours, 15.1 ± 7.7 hours, and 15.8 ± 8.6 hours, respectively).

Conclusions and Clinical Relevance—Pharmacokinetic data may provide useful information for use of meloxicam in Hispaniolan Amazon parrots. A mean plasma concentration of 3.5 μg/mL would be expected to provide analgesia in Hispaniolan Amazon parrots; however, individual variation may result in some birds having low plasma meloxicam concentrations after IV, IM, or oral administration. After oral administration, meloxicam concentration slowly reached the target plasma concentration, but that concentration was not sustained in most birds.

Control of pain and consideration of the available pain management options are important to the practice of avian medicine because of acute or chronic pain and inflammation in birds. Nonsteroidal anti-inflammatory drugs are commonly used as analgesics because of their anti-inflammatory and antinociceptive effects on peripheral and central tissues.1,2 Pain is a consequence of inflammation and sensitization of nerve endings at the site of tissue injury as a result of inflammatory mediators, such as prostaglandins, and reactions mediated by COX-1 and COX-2. Nonselective NSAIDs provide analgesia by blocking the action of both COX-1 and COX-2.3 The COX enzymes are found in avian tissues and are thought to function both peripherally and centrally in a manner similar to those in mammals.4,5 However, there may be considerable differences among species with regard to the relative COX-1 or COX-2 selectivity of certain drugs as well as differences in selectivity between in vivo and in vitro pharmacodynamic assays.4,5

Pharmacokinetics and toxicological effects of NSAIDs, such as meloxicam, sodium salicylate, and flunixin, have been evaluated in a few avian species, including chickens,4,6–9 mallard ducks,9,10 vultures,11–13 psittacine birds,14,15 Coturnix quail (Coturnix japonica),16 pigeons,9,17 ostriches, and turkeys.9 The relative expression of COX-1 and COX-2 differs among avian species.3 Moreover, these studies8,9 revealed that metabolism and plasma concentrations differ for each NSAID and species evaluated.

Meloxicam is one of the most frequently prescribed NSAIDs for companion birds in large part because of ease of administration, given that oral and injectable formulations are commercially available at concentrations amenable for use in small patients. Meloxicam typically is administered at an empirical dose range of 0.1 to 1.0 mg/kg.18,19 A pharmacodynamic study20 was conducted to evaluate the analgesic effect of meloxicam administered at 0.25 to 1.0 mg/kg IM in Hispaniolan Amazon parrots (Amazona ventralis) with experimentally induced arthritis. In that study,20 the highest dose evaluated (1 mg/kg) provided the most effective analgesia for up to 12 hours. However, pharmacokinetic studies are needed to correlate plasma concentrations of meloxicam with dosages identified as analgesic in earlier pharmacodynamic studies and to compare plasma concentrations when meloxicam is administered by IM, IV, and oral routes.

The objective of the study reported here was to evaluate the pharmacokinetics after IV, IM, and oral administration of meloxicam to Hispaniolan Amazon parrots. The dose of meloxicam has provided analgesia for experimentally induced inflammatory arthritis in parrots for up to 12 hours after IM administration.20 Pharmacokinetic data can be used to determine whether doses currently administered parenterally or orally reach plasma concentrations thought to be analgesic. To the authors' knowledge, there are no published data on the pharmacokinetics of meloxicam after oral administration to any avian species.

Materials and Methods

Animals—Eleven adult (4 to 20 years old; median, 7.25 years) Hispaniolan Amazon parrots of unknown sex were used in the study. Body weights ranged between 258 and 313 g. Various combinations of 8 of the 11 birds were used to comprise 3 experimental groups. During the study, parrots were housed in pairs or individually in stainless steel cages (61.0 × 61.0 × 63.5 cm) with a perch and 1 or 2 hanging toys in each cage. Parrots were fed a pelleted dieta formulated for psittacine birds and provided water ad libitum. The research protocol was approved by the Institutional Animal Care and Use Committee of the University of Wisconsin School of Veterinary Medicine.

Meloxicam administration and blood collection—A 3-period crossover design was used such that each parrot received a single dose of meloxicam via IV, IM, or oral administration. Time of meloxicam administration was designated as time 0 during the collection period. For each period, the baseline (before drug administration) sample was collected 7 or 8 days before meloxicam administration to minimize short-term blood loss. There was a minimum 2-week washout period between subsequent treatments.

In period 1, 8 parrots received a single dose (1 mg/kg) of meloxicamb (5 mg/mL) via IV administration into the right or left medial metatarsal vein. Each dose of meloxicam was administered with a 0.3-mL syringe and 27-gauge needle. Eleven blood samples (0.25 mL/sample; total volume, < 1.0% of body weight) were collected from each bird at 5, 15, and 30 minutes and 1, 2, 4, 6, 8, 12, and 24 hours after administration. Parrots were manually restrained for venipuncture, and blood samples were collected with a 1.0-mL syringe and 27-gauge needle from the right or left jugular vein, right or left basilar vein, or the contralateral medial metatarsal vein that had not been used for meloxicam administration. After collection of the blood sample at 6 hours, each parrot received 9 mL of lactated Ringer's solutionc SC divided between the right and left inguinal region because no parrots had been observed eating or drinking despite having access to food and water during the sample collection period.

In period 2, the same 8 parrots as in period 1 received a single dose (1 mg/kg) of meloxicamb (5 mg/mL) via IM administration into the left pectoral muscle. Each dose of meloxicam was administered with a 0.5-mL syringe and 27-gauge needle. Twelve blood samples (0.25 mL/sample) were collected from each bird from the previously described blood vessels. Samples were collected at 5, 15, and 30 minutes and 1, 2, 4, 6, 8, 12, 24, and 48 hours after drug administration. Similar to period 1, each parrot received 9 mL of lactated Ringer's solutionc SC divided between the right and left inguinal region after collection of the blood sample at 6 hours because no parrots had been observed eating or drinking despite having access to food and water during the sample collection period.

In period 3, 8 parrots (5 that were used in periods 1 and 2, and 3 that had not been used during those periods) received a single dose (1 mg/kg) of meloxicamd (1.5 mg/mL oral suspension) orally. Each dose of meloxicam (volume, 0.19 to 0.20 mL) was administered via an 18-gauge metal gavage tube placed into the crop. Drug administration was followed by infusion of 1 mL of water to flush the gavage tube. Eleven blood samples (0.25 mL/sample) were collected from the previously described blood vessels at 1, 2, 4, 6, 12, 24, 36, 48, 60, and 72 hours after drug administration. No fluids were administered to the parrots during this period because they were observed voluntarily eating and drinking during the sample collection period.

For all periods, blood samples were stored in 1-mL lithium heparin tubes.e Within 60 minutes after blood collection, samples were centrifuged at 2,400 × g for 8 to 10 minutes. Plasma was decanted into polypropylene cryogenic vials,f which were labeled and then frozen at −70°C until shipped to the laboratory of one of the authors (MHC) for measurement of drug concentrations.

Measurement of meloxicam concentrations—Plasma concentrations of meloxicam were determined via a validated HPLC technique in accordance with a method described elsewhere,21 with modifications. Briefly, extractions were performed in 1.5-mL polypropylene tubes by adding 100 μL of plasma, 30 μL of 1N HCl, 10 μL of piroxicam (1 mg of piroxicam/mL of methanol; piroxicam served as an internal standard), and 1 mL of diethyl ether. Samples were mixed on a vortexer for 5 seconds. Then, the upper organic layer was transferred to a fresh 2-mL polypropylene tube, whereas the lower aqueous layer was re-extracted via vortexing and centrifugation (as previously described) with another 1 mL of diethyl ether. The upper organic layer after the second extraction was harvested and added to the 2-mL polypropylene tube. Tubes were evaporated to dryness in a centrifugal evaporator.g The residue was redissolved in 200 μL of HPLC mobile phase (35% acetonitrile and 65% acetic acid in water), and 50-μL aliquots were analyzed via HPLC. The HPLC apparatus consisted of an HLPC systemh (pump setting, 0.3 mL/m) with a 4μM 150 × 2.0-mm C18 reverse-phase columni and UV absorbance detector set at a wavelength of 355 nm. Approximate retention times of piroxicam (internal standard) and meloxicam were 7 and 19 minutes, respectively. The 19-minute retention time allowed for complete separation of analytes from background peaks. Calibration curves were prepared by spiking blank plasma samples with 10 μL of meloxicam dissolved in methanol to achieve concentrations ranging from 0.1 to 25 μg/mL of plasma. Standard curves were linear (R2 > 0.99), and measurement of quality-control samples spiked with meloxicam at 0.25 or 25 μg/mL revealed good precision (coefficient of variation, < 25%) and accuracy (< 20%). The lower limit of quantitation of the assay was 0.1 μg/mL. Because of the limited volume of plasma available for each sample and the good precision and accuracy of the assay, unknown samples were assayed only once (ie, duplicate analyses were not performed).

Pharmacokinetic analysis—Pharmacokinetic values were derived from plasma concentration-versus-time data for each parrot and each route of administration via standard noncompartmental analysis with a commercial program.j Derived variables included initial plasma concentration (IV administration only), maximum plasma concentration (IM and oral administration only), time of maximal plasma concentration (IM and oral administration only), elimination half-life (IV administration only), volume of distribution (IV administration only), area under the plasma concentration-versus-time curve from time 0 to the last measured concentration, AUC0–∞, clearance (IV administration only), and systemic bioavailability (IM and oral administration only). Systemic bioavailability for IM and oral administration was calculated by dividing AUC0–∞ after IM or oral administration by the AUC0–∞ after IV administration for individual parrots that had received meloxicam via both the IV and IM routes (8 parrots) or both the IV and oral routes (5 parrots). A population estimate of bioavailability was also obtained by dividing the group median AUC0–∞ after IM or oral administration by the median AUC0–∞ after IV administration.

Results

The plasma concentration–time profiles for each of the 8 parrots after IV, IM, and oral administration of a single dose (1.0 mg/kg) of meloxicam were plotted (Figure 1). Mean ± SD plasma concentrations at various time points for each route of administration were also plotted (Figure 2).

Figure 1—
Figure 1—

Plasma concentration–time profiles after IV (A), IM (B), and oral (C) administration of a single dose of meloxicam (1.0 mg/kg) to 8 Hispaniolan Amazon parrots (Amazona ventralis). Time of meloxicam administration was designated as time 0. Each symbol represents results for 1 parrot. Notice that the same 8 parrots received meloxicam via IV and IM administration (A and B), but only 5 of these 8 received the drug orally (ie, 3 other parrots received the meloxicam only via oral administration [C]). Notice that the scales on the x- and y-axes differ among panels.

Citation: American Journal of Veterinary Research 74, 3; 10.2460/ajvr.74.3.375

Figure 2—
Figure 2—

Mean ± SD plasma meloxicam concentrations at various times after IV (gray circles), IM (white squares), and oral (black triangles) administration of a single dose of meloxicam (1 mg/kg) to Hispaniolan Amazon parrots (n = 8 parrots/treatment). Time of meloxicam administration was designated as time 0. The target concentration of 3.45 μg/mL, which is a concentration known to result in analgesia in Hispaniolan Amazon parrots,20 is indicated (dashed line).

Citation: American Journal of Veterinary Research 74, 3; 10.2460/ajvr.74.3.375

Derived pharmacokinetic variables were summarized (Table 1). The IM route of administration resulted in the greatest degree of variation in plasma concentrations of meloxicam among parrots during the first 8 hours after drug administration. Mean ± SD plasma concentrations at 12 hours after administration were similar for the IV (3.7 ± 2.5 μg/mL) and IM (3.5 ± 2.2 μg/mL) routes. Lower meloxicam concentrations were detected after oral administration, with peak concentrations achieved at a mean of 5 hours (range, 2 to 12 hours). Elimination half-life was similar among the routes of administration, with values of 15.9 ± 4.4 hours for IV administration, 15.1 ± 7.7 hours for IM administration, and 15.8 ± 8.6 hours for oral administration. The volume of distribution was low after IV administration (232 ± 220 mL/kg), which was consistent with limited extravascular distribution of the drug. Drug clearance after IV administration was also relatively low (12.2 ± 13.7 mL/kg/h), which was consistent with the relatively long elimination half-life. Finally, the systemic availability of meloxicam after IM administration was essentially complete (mean, 100%), which was consistent with good absorption into the circulation from administration sites. However, the availability after oral administration was slightly lower (range, 49% to 75%).

Table 1—

Pharmacokinetic values determined for Hispaniolan Amazon parrots (Amazona ventralis) after IV, IM, and oral administration of a single dose of meloxicam (1 mg/kg).

VariableIVIMPO
MeanSDRangeMeanSDRangeMeanSDRange
C0 (μg/mL)17.39.06.5–34
Cmax (μg/mL)10.51.49.1–133.71.11.9–5.5
Tmax (h)1.42.30.1–6.05.03.22.0–12
t1/2el (h)15.94.47.6–2315.17.71.8–2615.88.62.9–25
Vd (mL/kg)23222095–702
AUC0-last (h•μg/mL)1045419–1641468619–2711026214–188
AUC0–∞ (h•μg/mL)16910525–32117511621–3751137115–209
Plasma clearance (mL/kg/h)12.213.73.1–39
F (%)
   Individual*1.000.250.59–1.430.620.110.49–0.75
   All1.040.67

Meloxicam was administered to 8 parrots/treatment.

Value for F was calculated by dividing AUC0–∞ after IM or oral administration by AUC0–∞ after IV administration.

Value for F was calculated by dividing the mean AUC0–∞ after IM or oral administration by the mean AUC0–∞ after IV administration; the AUC0–∞ was measured for each parrot and includes all parrots receiving meloxicam via IM administration and 5 of 8 parrots receiving meloxicam via oral administration.

— = Value was not determined. AUC0–last = Area under the plasma concentration-versus-time curve to the last measured concentration. C0 = Initial concentration. Cmax = Maximum concentration. Tmax = Time of maximum concentration. t1/2el = Elimination half-life. Vd = Volume of distribution.

Discussion

The mean ± SD plasma concentration of meloxicam at 12 hours after IM administration was 3.5 ± 2.2 μg/mL, which is a concentration known to provide analgesia on the basis of a pharmacodynamic study20 of IM administration of meloxicam to Hispaniolan Amazon parrots. Intravenous administration of meloxicam resulted in a plasma concentration of 3.7 ± 2.5 μg/mL at 12 hours, which was similar to that for IM administration. Compared with disposition after IV administration, the disposition after IM administration was similar, with peak concentrations achieved rapidly after drug administration (median time of maximum concentration was 15 minutes), although the time of the maximum concentration in 1 parrot was 6 hours.

In contrast, oral administration resulted in slow attainment of the mean target plasma concentration of > 3.45 μg/mL by 6 hours. By 12 hours, the concentration had decreased below the predicted analgesic plasma concentration for Hispaniolan Amazon parrots. This suggested that higher doses are needed for oral administration to achieve blood concentrations equivalent to concentrations after IV or IM administration. A clinically relevant finding in the present study was the poor and highly variable bioavailability after oral administration of meloxicam, which suggested that IV or IM administration would be preferable to oral administration in Hispaniolan Amazon parrots. However, further studies are needed to evaluate tissue changes induced by repeated IM injections of meloxicam.

Some parrots had consistently low plasma meloxicam concentrations after IV, IM, and oral administration (1 parrot), IV and IM administration (1 parrot [oral administration was not provided to that parrot]), or oral administration (1 parrot that received meloxicam only via oral administration; Figure 1). Possible explanations for these observations include prior exposure to a hepatic-enzyme inducer, although no specific exposure was known, or perhaps a genetic polymorphism resulting in higher meloxicam clearance in these particular parrots. Regardless of the cause, analysis of these results suggested that some parrots treated with meloxicam at a dose of 1 mg/kg may not achieve predicted effective plasma concentrations of meloxicam. Further studies are needed to confirm these findings in a larger population of parrots.

In contrast to results of the present study, meloxicam administered orally to vultures had a high relative bioavailability of 107%, compared with concentrations after IM administration of meloxicam. The reasons for high bioavailability in vultures may be an artifact of rapid absorption.9 Mean ± SD elimination half-life for meloxicam in the Hispaniolan Amazon parrots of the present study was 15.9 ± 4.4 hours, 15.1 ± 7.7 hours, and 15.8 ± 8.6 hours after IV, IM, and oral administration, respectively. This is substantially longer than the elimination half-life reported in vultures, which was 0.42 ± 0.1 hours and 0.32 ± 0.17 hours after IM and oral administration, respectively.11 Elimination half-life of meloxicam after IV administration was also longer than that reported in other avian species, including chickens (3.21 hours), pigeons (2.40 hours), turkeys (0.99 hours), ducks (0.72 hours), and ostriches (0.5 hours).9

Food was withheld from all parrots for 10 hours prior to meloxicam administration to ensure an empty crop for those receiving meloxicam via the oral route. All parrots had access to water and food during each of the study periods, but only birds with longer intervals between collection times after oral administration were observed eating and drinking during the first 6 hours after meloxicam administration. Therefore, fluids were not administered SC to the parrots after oral administration of meloxicam because volume depletion occurred over a greater time period. Parrots receiving meloxicam via IV or IM administration also received 9 mL of lactated Ringer's solution SC after collection of the blood sample at 6 hours. At that time, approximately 1.75 mL of blood had been removed from the vascular space, and administration of fluids was intended to replace this volume, in addition to providing the maintenance fluid requirement for 6 hours. This was expected to have minimal effect on the pharmacokinetic data because the injected fluids likely remained in the vascular space for a short time.

The commercial preparation of oral meloxicam used in the present study contained xylitol. The toxic effects of xylitol in birds are unknown.

All birds were clinically normal at the end of the study. No data on toxic effects were collected in the present study, although the authors' research group has investigated the effects of meloxicam administered at 2.0 mg/kg IM every 12 hours in Coturnix quail.16 There were no significant alterations in renal function and no histopathologic findings in the quail in that study,16 but muscle necrosis was evident at the injection sites, which would contraindicate repeated administration of meloxicam by the IM route.

The pharmacokinetic data generated in the present study for meloxicam at a dose of 1 mg/kg coupled with results of a pharmacodynamic study20 provides useful information about the clinical use of meloxicam for analgesia in this species of parrot. A mean plasma concentration of 3.5 μg/mL is expected to provide sufficient analgesia in Hispaniolan Amazon parrots; however, there will be individual variation such that some parrots may have low plasma meloxicam concentrations following IV, IM, or oral administration. A future concurrent pharmacokinetic and pharmacodynamic study with a larger population of parrots would help clarify whether lower plasma concentrations are associated with poor analgesia. A clinically relevant finding in the present study was the poor and highly variable bioavailability after oral administration of meloxicam such that a dose of 1 mg/kg administered orally may not provide sufficient analgesia for all Hispaniolan Amazon parrots.

ABBREVIATIONS

AUC0–∞

Area under the plasma concentration–versus-time curve from time 0 extrapolated to infinity

COX

Cyclooxygenase

HPLC

High-performance liquid chromatography

a.

Exact, Kaytee Products Inc, Chilton, Wis.

b.

Metacam solution for injection, Boerhinger Ingelheim Inc, St Joseph, Mo.

c.

Abbott Laboratories, North Chicago, Ill.

d.

Metacam oral suspension, Boerhinger Ingelheim Inc, St Joseph, Mo.

e.

BD, Franklin Lakes, NJ.

f.

Nalgene Labware, Thermo Fisher Scientific, Rochester, NY.

g.

SpeedVac, Thermo Fisher Scientific, Waltham, Mass.

h.

Agilent 1100, Agilent Technologies, Palo Alto, Calif.

i.

Synergi Fusion, Phenomenex, Torrence, Calif.

j.

WinNonlin, version 3.01, Pharsight Corp, St Louis, Mo.

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