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Title: Studies with non-steroidal anti-inflammatory drugs
Author: Galbraith, Elizabeth Ann
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1994
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Abstract:
The pharmacokinetics and serum thromboxane inhibition of four non-steroidal antiinflammatory drugs (NSAIDs) were determined after administration to dogs by the intravenous, subcutaneous and oral routes. Flunixin meglumine was first administered at three oral dose rates, 0.55, 1.10 and 1.65 mg/kg, to determine a likely suitable dose rate by this route. At each dose rate the mean maximum plasma concentration of drug (Cmax ) occurred between 1 and 2 hours. After 0.55, 1.10 and 1.65 mg/kg the Cmax increased approximately in relation to the dose rate and values were 2.77 +/- 0.63, 5.03 +/- 0.99 and 8.17 +/- 2.02 mug/ml respectively. The mean area under the plasma concentration versus time curve (AUC) was 9.01,14.62 and 25.98 mug/ml.h after 0.55, 1.10 and 1.65 mg/kg. Maximum mean inhibition of serum thromboxane (TxB2) was 91.47, 98.84 and 97.31 % and occurred between 1 and 2 hours. The area under the TxB2 inhibition versus time curve was not linearly related to dose rate and was determined to be 5238, 5952 and 6169 %.h respectively for 0.55, 1.10 and 1.65 mg/kg dose rates . On the basis of the findings from the oral experiments the 1.10 mg/kg dose rate was selected for study after intravenous and subcutaneous administration. The decline in plasma concentration of flunixin meglumine after intravenous administration was best described by a bi-exponential equation. The mean half life of elimination (t V26) in dogs was 2.97 hours and the mean volume of distribution at steady state (Vdss) was 189.23 +/- 46.70 ml/kg. The AUC from observed values after administration at a dose rate of 1.10 mg/kg was 20.47 +/- 2.60 mug/ml.h. Determination of the AUC after intravenous administration allowed calculation of the bioavailability (F) after oral administration. After normalisation for dose rate the bioavailability after oral administration of flunixin to dogs was 74.8, 60.66 and 69.8 %.for the 0.55, 1.10 and 1.65 mg/kg dose rates respectively, thus indicating that absorption was approximately linearly related to dose rate administered. The maximum mean inhibition of serum TxB2 after intravenous administration was 99.87 % (0.5 hours), and the area under the TxB2 inhibition versus time curve was 2148 %.h, approximately 36 % of the area under the TxB2 inhibition versus time curve obtained after the equivalent dose rate administered by the oral route. After subcutaneous administration at a dose rate of 1.10 mg/kg the Cmax of flunixin in plasma was 6.36 mug/ml, and this occurred at 0.92 hours. Bioavailability was excellent after subcutaneous administration, the AUC being 26.30 +/- 4.73 mug/ml.h (F= 101.09 %). The maximum mean inhibition of TxB2 after subcutaneous administration was approximately equal to that after intravenous administration (99.73 % at 1 hour), as was the area under the TxB2 inhibition versus time curve. This AUC was also approximately half of the AUC produced by the oral administration of the same dose rate. No adverse reactions were observed after administration of flunixin meglumine to dogs. After administration at a dose rate of 0.3 mg/kg by the intravenous route to dogs, the decline in plasma concentration of piroxicam was best described by a single exponential equation. The fit of the mathematically modelled best fit curve was very poor for all animals. The tV26 was calculated to be 40.16 hours and the Vdss calculated from observed data was 178.37 ml/kg. The observed AUC of piroxicam after intravenous administration was 47.39 mug/ml.h. The maximum mean inhibition of serum TxB2 was 96.85 % and this occurred at 0.25 hours after drug administration. The area under the mean TxB2 inhibition versus time curve was 5309 %.h. The Cmax of piroxicam after oral administration at a dose rate of 0.3 mg/kg was 1.35 +/- 0.11 M-g/ml, and occurred at 3.33 (+/- 1.09 hours). The AUC was 46.77 mug/ml.h showing that the oral bioavailability of piroxicam was excellent (F = 102.69 %). The mean maximum inhibition of serum TxB2 occurred at 1 hour and was lower than that measured after intravenous administration (72.45 +/-3.38 %). The AUC for mean TxB2 inhibition versus time was approximately 77 % of that after intravenous administration (4067 %.h). The intravenous administration of piroxicam was complicated by its poor aqueous solubility and the need to administer it in ethanol. Some symptoms typical of ethanol intoxication were noted after intravenous administration, however these did not persist beyond the first 30 minutes after drug administration. Large decreases in the number of blood platelets were also detected in dogs after intravenous administration of piroxicam. Although some improvement was noted throughout the sampling times, numbers had not returned to normal by the final sampling times. It is unlikely that this effect was as a result of piroxicam administration as a similar effect was not observed after oral administration of the drug. It is possible that the decrease in platelet numbers was a result of ethanol administration. However, previously recorded ethanol induced thrombocytopenia has only been been associated with chronic alcohol consumption. Piroxicam was otherwise well tolerated after administration to dogs by the intravenous and oral routes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.788629  DOI: Not available
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