Pharmacokinetics and Its Application to Dosage Design in Veterinary Medicine.

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Title: Pharmacokinetics and Its Application to Dosage Design in Veterinary Medicine.
Author: Kukanich, Stanley Patrick
Advisors: Ronald Baynes, Committee Member
B. Duncan X. Lascelles, Committee Member
Jim E. Riviere, Committee Chair
Mark G. Papich, Committee Co-Chair
Abstract: The use of analgesics in veterinary medicine has increased markedly over the last two decades. Despite their increased use, little objective data is available on the efficacy of current dosage recommendations. The purpose of this dissertation was to assess the pharmacokinetics of opioids in dogs and objectively measure their pharmacodynamics by using a non-invasive, non-lethal, mechanical threshold device (von Frey device). The pharmacokinetics of morphine were evaluated following oral and intravenous administration. Morphine was rapidly eliminated, poorly and erratically absorbed orally, and the active metabolite (morphine-6-glucuronide) was not detected. The von Frey (vF) device was well tolerated, caused no apparent tissue damage, and showed no evidence of tolerance or aversion when repeated hourly for 8 hours. Following morphine sulfate administration,1 mg/kg, as an intravenous injection, the effective plasma concentration to elicit a 50% maximal response (EC50) was 13.9 ± 2.4 ng/mL, and vF thresholds were significantly elevated above baseline values for 4 hours. Following an intravenous infusion of morphine, the EC50 was 29.5 ± 5.4 ng/mL and the lowest mean plasma concentration in which vF thresholds were significantly elevated compared to saline was 31.3 ± 6.0 ng/mL. Plasma morphine concentrations were variable at higher infusion rates. Following multiple intravenous morphine sulfate doses (0.5 mg/kg every 2 hours), the EC50 was 27.3 ± 7.4 ng/mL, and there were no significant pharmacokinetic differences between the first and last dose. There were no significant differences in a saline infusion group vf thresholds compared to the previous untreated group. The pharmacokinetics of methadone following intravenous and oral administration, and oral administration with omeprazole or ketoconazole were examined. Methadone exhibited a rapid clearance, short elimination half-life, and was not detected in plasma following oral administration. Methadone was not detected following oral administration with omeprazole and only detectable in one dog following oral administration with ketoconazole. The vf device objectively correlated morphine plasma concentrations with its antinociceptive effects in dogs. Methadone and morphine did not reach therapeutic concentrations following oral administration to dogs.
Date: 2006-01-12
Degree: PhD
Discipline: Comparative Biomedical Sciences

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