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Scholarly Works (39 results)

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UC Davis Electronic Theses and Dissertations (2022)

Morphine is a potent, effective analgesic that is used widely in both human and veterinary medicine. Metabolism of morphine by UDP glucuronidation conjugation creates two metabolically active glucuronide metabolites: morphine-6 glucuronide and morphine-3 glucuronide. Morphine and its metabolites have been extensively studied in human medicine, however their pharmacokinetics and pharmacodynamics have yet to be explored to the same extent in horses. Such studies would help contribute to more effective opioid use in equine medicine. Our laboratory previously published a paper identifying M3G and M6G as the major metabolites of morphine in horses. This study also confirmed previous reports of increased motor activity, muscle fasciculation, and flared nostrils following intravenous administration of high doses of morphine (0.2 mg/kg and 0.5mg/kg). Additionally, horses in all dose groups (0.05, 0.1, 0.2 and 0.5 mg/kg) had decreased gastrointestinal activity, a common side effect associated with morphine use. Other side effects associated with morphine use in horses include increased motor activity, increased respiratory rate, increased blood pressure, and muscle fasciculation. The first aim of this work was to characterize and correlate the pharmacokinetics and selected pharmacodynamics of morphine administration in horses. Additional characterization of the pharmacokinetics and pharmacodynamic effects of morphine and its metabolites would add to existing data describing the relative concentrations of the metabolites of M3G and M6G. A total of ten horses were administered a single intravenous dose of morphine: 0.05, 0.1, 0.2, or 0.5 mg/kg, or saline control and blood samples were collected and analyzed for morphine and metabolites by LC/MS/MS to conduct pharmacokinetic analysis. Pharmacodynamic data in the forms of step count, heart rate and rhythm, gastrointestinal borborygmi, fecal output, packed cell volume, and total protein was also assessed. Morphine-3 glucuronide (M3G) was the predominant metabolite detected, with concentrations exceeding those of morphine-6 glucuronide (M6G) at all time point. The results also included decreased gastrointestinal motility and increased central nervous excitation with a correlation between increasing doses of morphine, increases in M3G concentrations and adverse effects Findings from this study supported additional studies of administration of purified M3G and M6G to horses to directly characterize pharmacodynamic activity of these metabolites. The next aim was to characterize and correlate the pharmacokinetics and selected pharmacodynamics of purified M6G in horses. In part one, 3 horses received a single intravenous administration of saline, 0.5 mg/kg M6G and 0.5 mg/kg morphine. Blood samples were collected up to 96-hours post administration, concentrations of drug and metabolites measured, and pharmacokinetics determined. Behavioral and physiologic effects were recorded. In part two of this study, two horses, scheduled to be euthanized for other reasons, were administered 0.5 mg/kg M6G. Blood, CSF and various tissue samples were collected post administration and concentrations of drug determined. The clearance of M6G was more rapid and the volume of distribution at steady state smaller for M6G compared to morphine. A reaction characterized by head shaking, pawing and slight ataxia was observed immediately following administration of both morphine and M6G horses. Following M6G administration, the behaviors subsided rapidly and was followed by a longer period of sedation. Following administration, M6G was detected in the kidney, liver, CSF and regions of the brain. Results of the current student encourage further investigation of M6G as an analgesic in horses. The final aim was to characterize the invitro metabolism of morphine by determining metabolic enzymes responsible for the formation of M3G and M6G. This was accomplished by expressing four equine UGT variants: UGT1A1, UGT2A1, UGT2B31 and UGT2B4 Functionality of the enzymes was assessed using 4-methylumbelliferone, testosterone, diclofenac and ketoprofen. Recombinant enzyme, control cells, equine liver microsomes and human UGT2B7 supersomes were then incubated with morphine. Concentrations of metabolites were measured using liquid chromatography- tandem mass spectrometry and enzyme kinetics determined. UGT2B31 metabolized morphine to morphine-3-glucuronide and low concentrations of morphine-6-glucuronide. While UGT2B31 contributes to the glucuronidation of morphine; however, it is probably not the main metabolizing enzyme. These results warrant further investigation of equine UGTs, including expression of additional enzymes and further characterization of UGT2B31 as a contributor to morphine metabolism.

    Cover page: Pharmacokinetic and Pharmacodynamic Characteristics of Morphine and its Metabolites in Horses
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2022)

    Background

    Intra-articular corticosteroids, such as isoflupredone acetate, are commonly used in the treatment of joint inflammation, especially in performance horses. Following administration in a non-inflamed joints blood concentrations of isoflupredone were low and detectable for only a short period of time post-administration compared to synovial fluid concentrations. For some drugs, inflammation can affect pharmacokinetics, therefore, the goal of the current study was to describe the pharmacokinetics of isoflupredone acetate following intra-articular administration using a model of acute synovitis. Secondarily, pharmacodynamic effects, including effects on joint circumference, joint flexion, and lameness following intra-articular administration of isoflupredone acetate in the experimental model were described.

    Methods

    Sixteen horses received a single intra-articular dose of 8 mg of isoflupredone acetate or saline 12 h post-administration of lipopolysaccharide. Blood and urine samples were collected up to 72 h and synovial fluid for 28 days post-administration, drug concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Joint circumference, maximum angle of pain free joint flexion and lameness were evaluated prior to and post-treatment.

    Results

    The maximum isoflupredone plasma concentration was 2.45 ± 0.61 ng/mL at 2.5 ± 0.75 h and concentrations were less than the limit of quantitation by 72 h. Isoflupredone was below detectable concentrations in urine by 72 h post-administration in all horses and no longer detectable in synovial fluid by 96 h post-administration. Joint circumference was significantly decreased in the isoflupredone treatment group compared to the saline group at 24 and 48 h post drug administration. Pain free joint flexion was significantly different between the saline and isoflupredone treatment groups on day 4 post-treatment.

    Conclusions

    Synovial fluid concentrations and maximum plasma concentrations of isoflupredone differed slightly between the current study and a previous one describing administration into a non-inflamed joint, however, the detection time of isoflupredone in blood was comparable. Effects of isoflupredone on joint circumference and degree of pain free joint flexion suggest a short duration of effect with respect to alleviation of lipopolysaccharide induced synovitis, however, results of this study support future studies of the anti-inflammatory effects of intra-articular isoflupredone acetate.
      Cover page: Pharmacokinetics and pharmacodynamics of intra-articular isoflupredone following administration to horses with lipopolysaccharide-induced synovitis
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2023)
      BACKGROUND: Lidocaine is a local anesthetic that is sometimes administered in combination with epinephrine. The addition of epinephrine increases the time lidocaine remains at the site of administration, thus prolonging the duration of effect. Due to their potential to prevent the visual detection of lameness, the administration of local anesthetics is strictly regulated in performance and racehorses. Recent reports of positive regulatory findings for lidocaine in racehorses suggests a better understanding of the behavior of this drug is warranted. The objective of the current study was to describe serum and urine concentrations and the pharmacokinetics of lidocaine and its primary metabolites following administration in combination with epinephrine, as a palmar digital nerve block in horses. Twelve horses received a single administration of 1 mL of 2% lidocaine HCl (20 mg/horse) with epinephrine 1:100,000, over the palmar digital nerve. Blood samples were collected up to 30 h and urine samples up to 48 h post administration. Lidocaine and metabolite concentrations were determined by liquid chromatography- mass spectrometry and pharmacokinetic (non-compartmental and compartmental) analysis was performed. RESULTS: Serum concentrations of lidocaine and 3-hydroxylidocaine were above the LOQ of the assay at 30 h post administration and monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were below detectable levels by 24 and 48 h, respectively. In urine, lidocaine, MEGX and GX were all non-detectable by 48 h post administration while 3-hydroxylidocaine was above LOQ at 48 h post administration. The time of maximal concentration for lidocaine was 0.26 h (median) and the terminal half-life was 3.78 h (mean). The rate of absorption (Ka) was 1.92 1/h and the rate of elimination (Kel) was 2.21 1/h. CONCLUSIONS: Compared to previous reports, the terminal half-life and subsequent detection time observed following administration of lidocaine in combination with epinephrine is prolonged. This is likely due to a decrease in systemic uptake of lidocaine because of epinephrine induced vasoconstriction. Results of the current study suggest it is prudent to use an extended withdrawal time when administering local anesthetics in combination with epinephrine to performance horses.
        Cover page: Pharmacokinetics and metabolism of lidocaine HCl 2% with epinephrine in horses following a palmar digital nerve block.
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2024)
        INTRODUCTION: Dosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h. METHODS: A prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software. RESULTS: A two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5-19.6) ng/mL. The median total body clearance was 30.4 (19.8-36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2-7.8) L/kg; and terminal elimination half-life was 11.2 (7.6-24.3) h. CONCLUSION: Hydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.
          Cover page: Pharmacokinetics of a continuous intravenous infusion of hydromorphone in healthy dogs.
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2024)
          INTRODUCTION: Morphine is an effective analgesic in horses, however, IV administration at therapeutic doses has been shown to produce dose-dependent neuroexcitation and unwanted gastrointestinal effects. The analgesic effects of morphine have, at least in part, been attributed to the morphine-6-glucuronide (M6G) metabolite. Oral administration to horses results in comparable M6G concentrations to that achieved following IV administration of a therapeutic dose without the adverse effects. The anti-nociceptive effects have not yet been reported. In the current study the thermal anti-nociceptive effects of single and multiple oral doses of morphine were assessed. METHODS: Six horses received a single 0.2 mg/kg IV dose of morphine and multiple oral doses of 0.8 mg/kg morphine every 12 h for 4.5 days. Blood samples were collected throughout administration, morphine, and metabolite concentrations determined and pharmacokinetic analysis performed. Drug related behavior and physiologic responses were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency in response to the application of heat. RESULTS: The maximum concentrations of M6G were higher following oral administration compared to IV and the combined morphine and M6G concentrations exceeded that of IV administration starting at 2 h. Oral administration of 0.8 mg/kg morphine provided and maintained comparable anti-nociception effects to IV morphine with less adverse effects, following single and multiple doses. Morphine was well tolerated following oral administration with less excitation and minimal effects on gastrointestinal borborygmi scores compared to IV administration. DISCUSSION: Results of the current study warrant further investigation of the anti-nociceptive effects of oral morphine administration to horses.
            Cover page: Pharmacokinetics and thermal anti-nociceptive effects of oral morphine in horses.
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2023)
            The minimization of pain in research animals is a scientific and ethical necessity. Carprofen is commonly used for pain management in mice; however, some data suggest that the standard dosage of 5 mg/kg may not provide adequate analgesia after surgery. We hypothesized that a higher dose of carprofen in mice would reduce pain-associated behaviors and improve analgesia without toxic effects. A pharmacokinetic study was performed in mice given carprofen subcutaneously at 10 or 20 mg/kg. Plasma concentrations were measured at 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 48 h after dosing (n = 3 per time point and treatment). At these doses, plasma levels were above the purported therapeutic level for at least 12 and 24 h, respectively, with respective half-lives of 14.9 and 10.2 h. For the efficacy study, 10 mice per group received anesthesia with or without an ovariectomy. Mice were then given 5 or 10 mg/kg of carprofen, or saline subcutaneously every 12 h. Orbital tightening, arched posture, wound licking, rearing, grooming, nesting behavior, and activity were assessed before surgery and at 4, 8, 12, 24, and 48 h after surgery. The von Frey responses were assessed before and at 4, 12, 24, and 48 h after surgery. The efficacy study showed that all surgery groups had significantly higher scores for orbital tightening, arched posture, and wound licking than did the anesthesia-only groups at 4, 8, 12, and 24-h time points. At the 8 h time point, the surgery groups treated with carprofen had significantly lower arched posture scores than did the surgery group treated with saline only. No significant differences were found between carprofen treatment groups for rearing, grooming, von Frey, activity, or nesting behavior at any time point. These results indicate that subcutaneous carprofen administered at these doses does not provide sufficient analgesia to alleviate postoperative pain in female CD1 mice.
              Cover page: A Pharmacokinetic and Analgesic Efficacy Study of Carprofen in Female CD1 Mice.
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2020)

              Background

              Meperidine is a synthetic opioid that belongs to the phenylpiperidine class and is a weak mu receptor agonist. In horses there are a limited number of published studies describing the analgesic effects of systemically administered meperidine in horses. The objective of this study was to describe the pharmacokinetics, behavioral and physiologic effects and effect on thermal threshold of three doses of intravenously administered meperidine to horses. Eight University owned horses (four mares and four geldings, aged 3-8 years were studied using a randomized balanced 4-way cross-over design. Horses received a single intravenous dose of saline, 0.25, 0.5 and 1.0 mg/kg meperidine. Blood was collected before administration and at various time points until 96 hours post administration. Plasma and urine samples were analyzed for meperidine and normeperidine by liquid chromatography-mass spectrometry and plasma pharmacokinetics determined. Behavioral and physiologic data (continuous heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were collected at baseline through 6 hours post administration. The effect of meperidine administration on thermal nociception was determined and thermal excursion calculated.

              Results

              Meperidine was rapidly converted to the metabolite normeperidine. The volume of distribution at steady state and systemic clearance (mean ± SD) ranged from 0.829 ± 0.138-1.58 ± 0.280 L/kg and 18.0 ± 1.4-22.8 ± 3.60 mL/min/kg, respectively for 0.5-1.0 mg/kg doses. Adverse effects included increased dose-dependent central nervous excitation, heart rate and cutaneous reactions. Significant effects on thermal nociception were short lived (up to 45 minutes at 0.5 mg/kg and 15 minutes at 1.0 mg/kg).

              Conclusions

              Results of the current study do not support routine clinical use of IV meperidine at a dose of 1 mg/kg to horses. Administration of 0.5 mg/kg may provide short-term analgesia, however, the associated inconsistent and/or short-term adverse effects suggest that its use as a sole agent at this dose, at best, must be cautiously considered.
                Cover page: Meperidine pharmacokinetics and effects on physiologic parameters and thermal threshold following intravenous administration of three doses to horses.
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2016)
                  Cover page: Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2022)

                  Background

                  In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency.

                  Results

                  Morphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied.

                  Conclusions

                  The current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.
                    Cover page: Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2020)
                    Phenobarbital is a common drug used to manage epilepsy in goats. However, the recommended dose and dosing frequency are based on studies in dogs and horses. Studies describing the pharmacokinetics of phenobarbital when administered orally and assessing changes in behavior with concurrent electroencephalogram (EEG) readings are warranted in goats. The objectives of this study were to determine the bioavailability of orally administered phenobarbital and determine the effect of phenobarbital on brain activity using EEG in healthy goats. A cross-over design with 8 non-pregnant goats was performed. The goats were administered phenobarbital intravenously at 10 mg/kg, followed by a 2 week wash out period, and then administered phenobarbital, orally, at 10 mg/kg. Plasma sample determination of phenobarbital concentrations were collected at 13 time points. Continuous EEG readings with simultaneous video recording for 12 h was performed to determine the state of vigilance using a behavior scoring system prior to and after phenobarbital administration. Bioavailability of phenobarbital was 24.9%. Mean ± SD for half-life was similar between the oral (3.80 ± 0.826 h) and intravenous (4.0 ± 0.619 h) routes. Time to observed maximum concentration (Tmax), and maximum plasma concentration (Cmax) for the oral administration were 1.75 ± 0.46 h and 4,478.7 ± 962.4 ng/mL, respectively. Clearance was 152.5 ± 102.7 ml/h/kg. Area under the curve from zero to infinity (AUC0→∞) was 155,813 ± 218,448 and 38,763 ± 9,832 h*ng/mL for the intravenous and oral administration routes, respectively. Behavior score at 3 h after phenobarbital administration was different (P = 0.0002) from the score prior to administration for the oral administration route. In contrast, behavior scores before administration of phenobarbital and each time point after administration were not different (P >0.05) for the intravenous administration route or other oral administration route time points. Bioavailability of phenobarbital was poor, and the half-life was very short due to a high clearance. Doses >10 mg/kg should be considered when phenobarbital is administered orally in goats.
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