Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds

Butch KuKanich Department of Anatomy and Physiology, and Pharmacology, Clinical, Analytical and Toxicological Services (PharmCATS), College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Stacy L. Borum Department of Anatomy and Physiology, and Pharmacology, Clinical, Analytical and Toxicological Services (PharmCATS), College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Abstract

Objective—To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.

Animals—6 healthy Greyhounds, 3 male and 3 female.

Procedures—Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 ± 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software.

Results—Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds.

Conclusions and Clinical Relevance—Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.

Abstract

Objective—To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.

Animals—6 healthy Greyhounds, 3 male and 3 female.

Procedures—Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 ± 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software.

Results—Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds.

Conclusions and Clinical Relevance—Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.

Contributor Notes

Supported by the Analytical Pharmacology Laboratory, Department of Anatomy and Physiology, and College of Veterinary Medicine, Kansas State University.

Additional support provided by the Benjamin Kurz Fund at Kansas State University, NIH NCRR 5T35RR00706410; The Merck Company Foundation, Merck Research Laboratories; and Merial Animal Health.

The authors thank Jamie Stueve and Michelle Hubin for technical assistance.

Address correspondence to Dr. KuKanich.
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