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PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL · PDF file 2019-10-12 · PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL MELOXICAM TABLETS IN HEALTHY HORSES by KARIE VANDER WERF B.S.,

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  • PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL MELOXICAM TABLETS IN HEALTHY HORSES

    by

    KARIE VANDER WERF

    B.S., University of Florida, 2000 D.V.M., Ross University School of Veterinary Medicine, 2005

    A THESIS

    submitted in partial fulfillment of the requirements for the degree

    MASTER OF SCIENCE

    Department of Clinical Sciences College of Veterinary Medicine

    KANSAS STATE UNIVERSITY Manhattan, Kansas

    2013

    Approved by:

    Major Professor Elizabeth Davis, DVM, PhD, DACVIM

  • Copyright

    KARIE VANDER WERF

    2013

  • Abstract

    The first aim of the current study was to investigate the pharmacokinetics of oral

    meloxicam tablets and the gastrointestinal and renal effects after a 14-day treatment period.

    Meloxicam was orally administered to six adult horses once daily at a dosage of 0.6 mg/kg for 14

    consecutive days. Blood was collected prior to each administration and at 20 and 40 min, and 1,

    2, 4, 8, 12, and 24 hours after administration on days 1, 7, and 14 for the determination of

    meloxicam plasma concentrations by mass spectrometry. In addition, trough samples were taken

    on days 3 and 10. Complete blood count, serum biochemical analysis, urinalysis, and

    gastroscopy were performed at baseline and conclusion of the investigation.

    Complete blood count, serum chemistry, and urinalysis results were unchanged through

    the study period. Gastroscopy scores were not significantly increased. The Cmax was 1.82 ± 0.80

    µg/mL at Tmax 3.48 ± 3.30 hr on day 1, 2.07 ± 0.94 µg/mL at Tmax 1.24 ± 1.24 hr on day 7, and

    1.81 ± 0.76 µg/mL at 1.93 ± 1.30 h on day 14 (p = 0.30). The mean half-life was 4.99 ± 1.11 h.

    The second aim of the study was to compare the analgesic effects and gastrointestinal and

    renal adverse effects of oral meloxicam tablets (0.6 mg/kg) to oral phenylbutazone tablets (4.4

    mg/kg) orally once daily for 4 days in induced and naturally occurring lameness in adult horses.

    The study was performed on 4 healthy but lame adult horses. Complete blood count, serum

    biochemistry, urinalysis, and gastroscopy were performed prior to entrance to the study.

    Lameness was exacerbated in two horses using lipopolysaccharide (LPS; E. coli O55:B5)

    injected into the right metacarpophalangeal joint. The remaining two horses had Grade 3 or

    Grade 4 lameness due to naturally occurring laminitis. Meloxicam or phenylbutazone was

    administered to two horses each in a blinded, randomized manner once daily for four days.

    Lameness was evaluated using a pressure mat system and contact pressure, force, and stride

    length were evaluated at baseline and twice daily.

    Complete blood count, serum chemistry, and urinalysis were unremarkable for all four

    horses except one horse with an increased GGT. This horse experienced hepatic rupture

    secondary to amyloidosis the final day of the study. Gastric ulcer scores did not change during

    the study period. Phenylbutazone administration resulted in a greater response (force and contact

    area) in the right front and left hind limbs compared to meloxicam administration. There were

    not enough data points to evaluate the other two limbs.

  • A third aim of the study was two-fold and first evaluated the effects of ex vivo stimulation

    of peripheral blood mononuclear cells (PBMCs) with LPS on cyclooxygenase (COX)

    messenger RNA (mRNA) expression. The second portion documented the effects of LPS-

    induced joint inflammation and treatment with non-steroidal anti-inflammatory drugs on the

    mRNA and protein expression of COX-2 in PBMCs. The results indicate that LPS upregulates

    COX-2 gene expression in PBMCs. Additionally, injection of LPS into the metacarpophalangeal

    joint increases both COX-2 mRNA and protein expression in PBMCs at 24 hours after injection.

    The relative expression of COX-2 after treatment with meloxicam or phenylbutazone indicates a

    stronger inhibition with phenylbutazone; however, further study with additional horses is needed.

    Pharmacokinetic analysis of the oral tablet formulation of meloxicam indicates the

    pharmacokinetics are similar to the oral suspension formulation. Meloxicam appears to be

    inferior to phenylbutazone in its analgesic properties for induced lameness and naturally

    occurring laminitis, however the small sample size used in the study makes interpretation

    difficult.

  • v

    Table of Contents

    List of Figures ................................................................................................................................ vi  

    List of Tables ................................................................................................................................ vii  

    Acknowledgements ...................................................................................................................... viii  

    Dedication ...................................................................................................................................... ix  

    Chapter 1 - Introduction .................................................................................................................. 1  

    Chapter 2 - Literature Review ......................................................................................................... 3  

    Pharmacokinetics ........................................................................................................................ 3  

    Introduction ............................................................................................................................. 3  

    Principles of pharmacokinetic analysis ................................................................................... 5  

    Pharmacokinetic parameters ................................................................................................... 6  

    Non-steroidal anti-inflammatory drugs ...................................................................................... 9  

    Meloxicam ................................................................................................................................ 11  

    Synovitis models ....................................................................................................................... 15  

    Lameness Grades ...................................................................................................................... 16  

    Figures and Tables .................................................................................................................... 17  

    Chapter 3 - Materials and Methods ............................................................................................... 21  

    Aim 1 ........................................................................................................................................ 21  

    Experimental design and sample collection .......................................................................... 21  

    Statistical analysis ................................................................................................................. 22  

    Aim 2 ........................................................................................................................................ 23  

    Statistical analysis ................................................................................................................. 23  

    Aim 3 ........................................................................................................................................ 24  

    Chapter 4 - Results ........................................................................................................................ 25  

    Aim 1 ........................................................................................................................................ 25  

    Aim 2 ........................................................................................................................................ 26  

    Aim 3 ........................................................................................................................................ 29  

    Chapter 5 - Discussion .................................................................................................................. 33  

    References ..................................................................................................................................... 36  

  • vi

    List of Figures

    Figure 2.1 One compartment open pharmacokinetic model with first-order absorption. ............. 18  

    Figure 2.2 Generalized open two-compartment pharmacokinetic model with first-order

    absorption (K01) into and elimination (Kel) from the central compartment. K12 and K21

    represent intercompartmental micro-rate constants. ............................................................. 18  

    Figure 2.3 Three-compartment pharmacokinetic model after intravenous administration. ......... 18  

    Figure 2.4 The arachidonic acid cascade. HPETE = hydroperoxyeicosatetraenoic acid; HETE =

    hydroxyeicosatetraenoic acid; LT

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