Guinea pigs are commonly kept as pets and are widely used in biomedical research in many countries.1,2 They often undergo routine surgeries, such as ovariohysterectomy, in clinical practice and a variety of surgical procedures as part of research studies. There are only a few evidence-based recommendations for pain management in guinea pigs, and many dosage recommendations for analgesics are based on anecdotal information, clinical experience, or extrapolation from data for other species.3,4 Opioids are frequently used in veterinary medicine and are considered to be the most effective class of analgesic drugs for the management of perioperative pain. Hydromorphone is a semisynthetic full μ-opioid receptor agonist that has been extensively studied in other vertebrate species.5–7 It is recommended as a first-choice option for treatment of signs of moderate to severe pain in dogs and cats.8 However, in assessments9,10 of analgesia after administration of hydromorphone, the plasma drug concentrations that appear to be effective have varied. A plasma hydromorphone concentration between 2 and 3 ng/mL is expected to have antinociceptive effects in humans and in dogs.9,10
To the authors’ knowledge, there are no published studies evaluating the pharmacokinetic properties of hydromorphone in guinea pigs. The objective of the study reported here was to investigate the pharmacokinetics of hydromorphone hydrochloride after IV or IM administration of a single dose in healthy guinea pigs. It was hypothesized that administration of hydromorphone to guinea pigs would result in plasma concentrations similar to those reported as providing effective analgesia in other species.
Materials and Methods
Guinea pigs
Eight adult retired breeder (approx age, 2 years) Hartley guinea pigs (4 sexually intact males and 4 sexually intact females) that had a mean ± SD body weight of 0.97 ± 0.08 kg were enrolled in a crossover experimental trial. All guinea pigs were deemed healthy on the basis of results of a physical examination and a CBC. Guinea pigs were housed in same-sex pairs in plastic pens lined with commercial recycled paper pulp bedding.a The pens were kept in a temperature-controlled (20°C) room on a 12-hour light-dark cycle. Free access to grass-based hay, commercial guinea pig pellets, and water was provided as well as cardboard huts. Guinea pigs with a vascular access port systemb implanted in the right jugular vein prior to purchase were purchased from a commercial vendor.c This study was approved by the University of Saskatchewan Animal Research Ethics Board (No. 20170086), and experimental procedures adhered to the Canadian Council on Animal Care guidelines for humane animal use.
Procedures
A 3F polyurethane catheter with 0.07-mL dead volume had been placed in the jugular vein and connected to an external port located in the interscapular region of each guinea pig prior to purchase. The external port was wiped with 70% alcohol prior to use. A blunt-ended injector needled was inserted into the vascular access port to collect a blood sample with a 3-syringe method as follows: removal of dead volume (0.1 mL), collection of the blood sample (0.3 mL), followed by administration of a balanced crystalloid fluide (0.3 mL). Heparin-containing saline (0.9% NaCl) solution (0.1 mL; heparinf concentration, 4 U/mL) was used for flushing IV catheters to maintain patency between blood sample collections that were performed at intervals > 30 minutes. During intervals of ≥ 8 hours between blood sample collections, a heparin (500 U/mL) and 50% dextroseg solution (0.1 mL) was used as a lock solution to maintain IV catheter patency.
Guinea pigs were randomly assigned to receive 1 of the 2 treatments by use of a computer-generated list.h Hydromorphone hydrochloridei (2-mg/mL solution) at a dose of 0.3 mg/kg was either administered IV (designated as treatment HHIV) or IM (designated as treatment HHIM) to each guinea pig. Guinea pigs receiving treatment HHIV were anesthetized with isofluranej in oxygen in an acrylic chamber for the placement of an IV catheter on the morning of treatment administration. Food was not withheld from the guinea pigs prior to anesthesia; however, each guinea pig's oral cavity was cleaned with cotton-tipped applicators to remove food material prior to induction of anesthesia. Following induction of anesthesia, each guinea pig was removed from the chamber, and anesthesia was maintained via a face mask with isoflurane in oxygen delivered by use of a Bain system with a fresh gas flow of 1.5 L/min. A 26-gauge polypropylene IV catheterk (0.75 in) was placed aseptically in one of the cephalic veins selected by random choice. A light bandage was applied to cover the catheter, and the guinea pig was allowed to fully recover from anesthesia. The IV catheter was removed within 30 minutes after drug administration.
Each guinea pig was individually housed in a cage with access to food and water for the duration of the blood sample collection period. A sedation scale previously modified for guinea pigs was used.11 A sedation score was determined for each guinea pig immediately before handling for each blood sample collection. Investigators assigning a sedation score were aware of the treatment that the guinea pig had received.
For each treatment, the time of drug administration was designated as 0 minutes. For treatment HHIV, hydromorphone was administered via the cephalic catheter. Prior to and after drug administration the IV catheter was flushed with 0.3-mL balanced crystalloid fluid.e For treatment HHIM, each guinea pig was manually restrained and hydromorphone was administered randomly in the right or left epaxial musculature. The 26-gauge needlel (3/8 inch) was directed perpendicular into the muscle, and IM placement was confirmed by negative aspiration prior to drug administration.
A blood sample (0.3 mL each) was collected via the vascular access port immediately before and 5, 10, 15, 20, 30, 45, 60, 90, 120, 240, 360, 480, and 720 minutes after hydromorphone administration (at 0 minutes). Each blood sample was immediately transferred to a tube containing lithium heparin and placed on ice. All samples were centrifuged at 3,000 × g for 10 minutes within an hour after collection. Plasma was harvested and frozen at −80°C until analysis for hydromorphone and hydromorphone-3-glucuronide concentrations.
During the course of the entire study, the volume of blood removed from each guinea pig was calculated to be < 10% of the animal's total blood volume. There was a washout period of 7 days after the first treatment, and then each guinea pig underwent the other treatment.
Analysis of plasma samples
Hydromorphone concentration was quantified in guinea pig plasma by use of LC-MS/MS as described previously.12 Hydromorphone-3-glucuronide concentrations were determined with a previously published LC-MS/MS method.13 For each analyte, partial validation of the test method was performed with guinea pig plasma as the matrix. Calibrators and negative control (drug-free guinea pig plasma) samples were prepared fresh for each quantitative assay. Quality control samples (drug-free guinea pig plasma fortified with analyte at 3 concentrations that were considered high [200 ng/mL], medium [40 ng/mL], and low [0.30 ng/mL; 3 times the limit of quantification of the assay]) within the standard curve were included with each sample set as an additional check of accuracy.
For analysis, hydromorphone and hydromorphone-3-glucuronidem were combined into 1 working solution by dilution of stock solutions with methanol to concentrations of 0.01, 0.1, and 1 ng/μL. Plasma calibrators were prepared by dilution of the working standard solutions with drug-free guinea pig plasma to concentrations ranging from 0.10 to 600 ng/mL. Calibration curves and negative control samples were prepared fresh for each quantitative assay. Quality control samples (drug-free guinea pig plasma fortified with analyte at 3 concentrations that were considered high [200 ng/mL], medium [40 ng/mL], and low [0.30 ng/mL; 3 times the limit of quantification of the assay]) within the standard curve were included with each sample set as an additional check of accuracy.
Prior to analysis, 500 μL of each plasma sample was diluted with 500 μL of acetonitrile and 1M acetic acid (9:1 [vol:vol]) containing d3-hydromorphonel (internal standard; 0.1 ng/μL) to precipitate proteins. The samples were vortexed for 2 minutes to mix, refrigerated for 20 minutes, vortexed for an additional 1 minute, and centrifuged at 3,830 × g for 10 minutes at 4°C. Subsequently, 10 μL of the supernatant was injected into the LC-MS/MS system.
The concentrations of hydromorphone and hydromorphone-3-glucuronide in the plasma samples were measured by LC-MS/MS with positive heated electrospray ionization. Quantitative analysis of plasma was performed on a triple quadrupole mass spectrometern coupled with a liquid chromatography systemo and operated in laminar flow mode. The spray voltage was 3,500 V, the vaporizer temperature was 200°C, and the sheath and auxiliary gas were 45 and 30 (arbitrary gas flow units), respectively. Product masses and collision energies were optimized by infusing the standards into the mass spectrometer. Chromatography employed a 2.1 × 100-mm, 5-μm (pore size) columnp and a linear gradient of acetonitrile in water, both with 0.2% formic acid, at a flow rate of 0.40 mL/min. The initial acetonitrile concentration was held at 0% for 0.42 minutes, ramped to 30% over 3 minutes, and ramped to 95% over 0.41 minutes before being allowed to reequilibrate for 4 minutes.
Detection and quantification procedures were conducted with selective reaction monitoring of the initial precursor ion for hydromorphone (m/z, 286.1), hydromorphone-3-glucuronide (m/z, 462.1), and the internal standard d3-hydromorphone (m/z, 289.1). The response for the product ions for hydromorphone (m/z, 128.1, 157.1, and 185.1), hydromorphone-3-glucuronide (m/z, 286.2), and the internal standard d3-hydromorphone (m/z, 157.1 and 185.1) were plotted, and the peaks at the proper retention times were integrated with software.q This software was used to generate calibration curves and quantify analyte concentrations in all samples by linear regression analysis. A weighting factor of 1/X (where X refers to the calibrator concentration) was used for all calibration curves.
Linearity was established over the concentration range of 0.1 to 300 ng/mL and 0.1 to 600 ng/mL for hydromorphone and hydromorphone-3-glucuronide, respectively, and the correlation coefficients were ≥ 0.99. The accuracy and precision of the assay were determined by assaying quality control samples in replicates (n = 6). Accuracy was reported as percentage nominal concentration, and precision was reported as percentage relative SD. For hydromorphone, accuracy was 98%, 110%, and 91% for concentrations of 0.30 ng/mL, 40 ng/mL, and 200 ng/mL, respectively; precision was 12%, 7%, and 7% for concentrations of 0.30 ng/mL, 40 ng/mL, and 200 ng/mL, respectively. For hydromorphone-3-glucuronide, accuracy was 92%, 89%, and 109% for concentrations of 0.30 ng/mL, 40 ng/mL, and 200 ng/mL, respectively; precision was 9%, 7%, and 5% for concentrations of 0.30 ng/mL, 40 ng/mL, and 200 ng/mL, respectively. The technique was optimized to provide a limit of quantitation of 0.1 ng/mL for both the parent drug and the metabolite.
Pharmacokinetic analysis
For the 2 routes of administration, plasma hydromorphone and hydromorphone-3-glucuronide concentration-versus-time data underwent noncompartmental analysis with a commercially available software program.r Maximum drug concentrations and time to maximal drug concentration were obtained directly from the analyte concentration data. Calculated pharmacokinetic parameters included λz, terminal-phase half-life, area under the curve from time 0 to infinity, percentage of the AUC that was extrapolated, bioavailability, systemic clearance, and volume of distribution at steady state by use of various formulas (Appendix).
Statistical analysis
Statistical analyses were performed to assess differences in mean residence time between treatments. Normal distribution of pharmacokinetic data was verified with the Shapiro-Wilk test. Owing to violation of the normality assumption, the Wilcoxon signed rank test was used. Significance was set at a value of P < 0.05.
Results
No clinically apparent adverse effects were observed in any guinea pigs following hydromorphone administration by either route. Pharmacokinetic data were available for 8 guinea pigs after treatment HHIM. Pharmacokinetic data were available for 7 guinea pigs following treatment HHIV owing to failure of the vascular access port in 1 guinea pig.
Pharmacokinetic parameters were calculated and the plasma concentration-versus-time curves for hydromorphone hydrochloride and hydromorphone-3-glucuronide were plotted (Figure 1). Following treatment HHIV, the mean plasma hydromorphone concentration remained ≥ 4 ng/mL for 2 hours and had decreased to < 2 ng/mL at 4 hours. Following treatment HHIM, the mean plasma hydromorphone concentration remained ≥ 4 ng/mL for 4 hours and had decreased to < 2 ng/mL at 6 hours. Other pharmacokinetic data for the 2 treatments were summarized (Table 1). Mean residence time was longer (P = 0.016) after guinea pigs received treatment HHIM than after they received treatment HHIV. All guinea pigs had a sedation score of 0 at all time points after hydromorphone administration.
Mean ± SD natural log plasma hydromorphone (A) and hydromorphone-3-glucuronide (B) concentrations following a single dose of 0.3 mg of hydromorphone/kg administered IV (black circles) or IM (white circles) to 8 guinea pigs in a crossover study. Data were available for 7 guinea pigs following IV administration because of failure of the vascular access port in 1 guinea pig.
Citation: American Journal of Veterinary Research 81, 4; 10.2460/ajvr.81.4.361
Mean ± SD pharmacokinetic parameters for hydromorphone and hydromorphone-3-glucuronide following a single dose of 0.3 mg of hydromorphone/kg administered IV or IM to 8 guinea pigs in a crossover study.
| Hydromorphone | Hydromorphone-3-glucuronide | |||
|---|---|---|---|---|
| Parameter | IV (n = 7) | IM (n = 8) | IV (n = 7) | IM (n = 8) |
| C0 (ng/mL) | 263.2 ± 60.5 | NA | NC | NC |
| Cmax (ng/mL) | NA | 171.9 ± 29.4 | 457.4 ± 99.2 | 511.1 ± 185.1 |
| Tmax (h) | NA | 0.12 ± 0.04 | 0.45 ± 0.48 | 0.68 ± 0.30 |
| λz (1/h) | 0.345 ± 0.219 | 0.608 ± 0.326 | 0.380 ± 0.068 | 0.478 ± 0.097 |
| Cl (mL/min/kg) | 52.8 ± 13.5 | NA | NC | NC |
| Vdss (L/kg) | 2.39 ± 0.479 | NA | NC | NC |
| AUCinf (ng·h/mL) | 100 ± 26.8 | 134 ± 53.3 | 869 ± 248 | 1,291 ± 582 |
| AUCextrap (%) | 0.393 ± 0.467 | 0.183 ± 0.196 | 2.39 ± 0.479 | 0.611 ± 0.429 |
| F (%) | NA | 133 ± 55.0 | NC | NC |
| MRT (h) | 0.773 ± 0.141 | 0.994 ± 0.335 | 2.04 ± 0.470 | 2.14 ± 0.443 |
| MAT (h) | NA | 0.221 ± 0.227 | NC | NC |
Data were available for 7 guinea pigs following IV administration because of failure of the vascular access port in 1 guinea pig. All pharmacokinetic values were generated by noncompartmental analysis.
AUCextrap = Percentage of the AUC that was extrapolated to infinity. AUCinf = Area under the curve from 0 minutes (time 0) to infinity. C0 = Drug concentration at 0 minutes (time 0). Cl = Total systemic clearance. Cmax = Maximal plasma concentration. F = Bioavailability. λz = Slope of the terminal portion of the plasma concentration-versus-time curve. MAT = Mean absorption time. MRT = Mean residence time. NA = Not applicable. NC = Not calculated. Tmax = Time of maximal plasma concentration. Vdss = Volume of distribution at steady state.
Discussion
Results of the present study indicated that hydromorphone had a high bioavailability and rapid elimination after IM administration in guinea pigs. Maximum concentration was achieved rapidly (0.12 hours) following IM administration. The rapid increase in plasma concentration following treatment HHIM could be associated with a rapid onset of clinical effects provided the drug effect is correlated with plasma concentration. Although hydromorphone reportedly is highly bioavailable following extravascular administration in other species,6,14 the calculated bioavailability > 10 0 % fol lowing IM administration in the present study was likely erroneous. Bioavailabilities > 100% have been reported in the veterinary medical literature, but these findings were most likely attributable to experimental error related to study design, study executions, or sample analysis.15 After careful evaluation, the definitive reason for the overestimation of bioavailability of hydromorphone following IM administration in the present study remained unclear. In the guinea pigs following treatment HHIV, the volume of distribution at steady state for hydromorphone was comparable to that reported for cats but smaller than that reported for dogs.6,7 The systemic clearance for hydromorphone was high but similar to the reported hepatic blood flow in guinea pigs (46 mL/min/850 g of body weight).16 Results of previous studies6 in dogs have suggested that extrahepatic metabolism of hydromorphone occurs in that species.
In the present study, the plasma hydromorphone concentrations in the guinea pigs remained ≥ 4 ng/mL for 2 hours after treatment HHIV and for 4 hours after treatment HHIM. Plasma hydromorphone concentration ≥ 4 ng/mL is greater than concentrations considered to be analgesic in other species.9,10 However, in addition to being species dependent, therapeutic hydromorphone plasma concentrations among animals may vary depending on the type and degree of pain, individual-specific response to the drug, concurrent illnesses, or ongoing treatments with other medications. In a clinical study17of humans with chronic severe pain, plasma concentrations of hydromorphone > 4 ng/mL were associated with analgesia. In another study9 evaluating human patients, a plasma concentration of 2 ng of hydromorphone/mL was expected to have antinociceptive effects. In the guinea pigs of the present study, plasma concentration of hydromorphone decreased to < 2 ng/mL at 4 hours after treatment HHIV and at 6 hours after treatment HHIM.
It is important to note that the duration of the antinociceptive effect of opioids does not necessarily correlate with plasma drug concentration. The reason for this is that drug concentrations at the receptor level lag behind plasma concentrations. To determine effective analgesia, pharmacodynamic studies are needed. For example, in cats following hydromorphone administration, thermal antinociception was evident for 450 minutes, whereas plasma concentrations were < 1 ng/mL after 360 minutes.7 The range for antinociceptive hydromorphone plasma concentration in guinea pigs is unknown, and pharmacodynamic species-specific analgesiometric testing would be needed to develop evidence-based dosing recommendations for this drug in this species.
In humans and rats, hydromorphone is eliminated primarily as metabolites including dihydromorphine, dihydroisomorphine, dihydromorphone-3-glucuronide, hydromorphone-3-glucuronide and dihydromorphone-6-glucuronide, of which dihydromorphone-3-glucuronide is the predominant metabolite.18,19 In the present study, hydromorphone-3-glucuronide in plasma was detectable immediately after drug administration by either route and up to the last time point. In rats, hydromorphone-3-glucuronide reportedly has no analgesic activity but does appear to have neuroexcitatory effects.20,21 Although signs of neuroexcitation were not observed in the guinea pigs of the present study, characterization of the pharmacological effects of this metabolite in guinea pigs requires further investigation. The short time to maximal plasma concentration of hydromorphone-3-glucuronide and the high systemic clearance of hydromorphone in guinea pigs indicated a likely need for dosing with hydromorphone at frequent intervals in clinical situations.
In the present study, no sedation or clinically apparent adverse effects were observed after IV or IM administration of hydromorphone at a dose of 0.3 mg/kg in any of the guinea pigs. In other species, frequently observed adverse effects associated with hydromorphone administration are nausea, vomiting, respiratory depression, CNS depression, and bradycardia. No monitoring of cardiovascular or respiratory variables was implemented in the present study, and the cardiorespiratory effects of hydromorphone in guinea pigs remain to be evaluated.
The pharmacokinetic data for hydromorphone following IV or IM administration obtained from guinea pigs in the present study were similar to data for other species. Results of the present study have suggested that hydromorphone should be administered frequently to maintain antinociceptive effects in this species. Additional studies to evaluate the effects of different doses and routes of administration of hydromorphone as well as the analgesic benefits of such treatments in guinea pigs are needed.
Acknowledgments
Supported by the Canadian Association for Laboratory Animal Medicine and Canadian Association for Laboratory Animal Surgery, Canada.
The authors declare that there were no conflicts of interest.
ABBREVIATIONS
| LC-MS/MS | Liquid chromatography–tandem mass spectrometry |
Footnotes
Carefresh, Healthy Pet, Ferndale, Wash.
Vascular access buttons, VAB95BS, Instech Laboratories, Plymouth Meeting, Pa.
Charles River Laboratories, Kingston, NY.
VAH6M-50, Instech Laboratories, Plymouth Meeting, Pa.
Normosol-R, Hospira, Montreal, QC, Canada.
Heparin sodium injection USP, Sandoz, Boucherville, QC, Canada.
Vetoquinol, Lavaltrie, QC, Canada.
GraphPad Prism, Version 6, GraphPad Software Inc, La Jolla, Calif.
Hydromorphone HCl, Sandoz, Boucherville, QC, Canada.
Isoflurane, Baxter Corp, Mississauga, ON, Canada.
AniCath, nonwinged IV cannula, Millpledge Veterinary Canada, Toronto, ON, Canada.
BD Precision Glide Needle, BD, Franklin Lakes, NJ.
Cerilliant Corp, Round Rock, Tex.
TSQ Vantage triple quadrupole mass spectrometer, Thermo Scientific, San Jose, Calif.
LC-10ADvp, Shimadzu Corp, Kyoto, Japan.
TFC TLX4, Thermo Scientific, San Jose, Calif.
Zorbax Eclipse-XDB-Phenyl 2.1 × 100-mm, 5-μm column, Agilent Technologies Inc, Santa Clara, Calif.
Phoenix WinNonlin, version 6.2, Certara USA Inc, Princeton, NJ.
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Appendix
Formulas used to calculate pharmacokinetic parameters in a study of the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in guinea pigs (Cavia porcellus)
| Parameter | Formula |
|---|---|
| Terminal half-life | 0.693/λz |
| AUCinf | AUClast + Clast/λz, where AUClast was calculated with the trapezoidal rule |
| AUCextrap | ([AUCinf – AUClast]/AUCinf) × 100 |
| F | AUCIM/AUCIV |
| Cl | Dose/AUCinf |
| Vdss | MRTinf × Cl |
| MRT | AUMCinf/AUCinf |
AUCextrap = Percentage of the AUC that was extrapolated to infinity. AUCIM = Area under the curve for the IM route of administration. AUCinf = Area under the curve from 0 minutes (time 0) to infinity. AUCIV = Area under the curve for the IV route of administration. AUClast = Area under the curve from 0 minutes (time 0) to the last time point measured. AUMCinf = Area under the moment curve from 0 minutes (time 0) to infinity. Cl = Total systemic clearance. Clast = Concentration at last time point measured. F = Bioavailability. MRT = Mean residence time. MRTinf = Mean residence time from 0 minutes (time 0) to infinity. Vdss = Volume of distribution at steady state.
