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Effect of oral administration of low doses of pentobarbital on the induction of cytochrome P450 isoforms and cytochrome P450-mediated reactions in immature Beagles

Joseph C. KawalekOffice of Research, Center for Veterinary Medicine, Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708.

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Karyn D. HowardOffice of Research, Center for Veterinary Medicine, Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708.

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Dorothy E. FarrellOffice of Research, Center for Veterinary Medicine, Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708.

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Janice DerrNew Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug Administration, Metro Park North, 7500 Standish Pl, Rockville, MD 20855.

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Carol V. CopeOffice of Research, Center for Veterinary Medicine, Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708.

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Jean D. JacksonOffice of Research, Center for Veterinary Medicine, Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708.

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Michael J. MyersOffice of Research, Center for Veterinary Medicine, Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708.

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Abstract

Objective—To determine the effect of oral administration of low doses of pentobarbital on cytochrome P450 (CYP) isoforms and CYP-mediated reactions in immature Beagles.

Animals—42 immature (12-week-old) Beagles.

Procedure—Dogs were grouped and treated orally as follows for 8 weeks: low-dose pentobarbital (50 µg/d; 4 males, 4 females), mid-dose pentobarbital (150 µg/d; 4 males, 4 females), high-dose pentobarbital (500 µg/d; 4 males, 4 females), positive-pentobarbital control (10 mg/kg/d; 2 males, 2 females), positivephenobarbital control (10 mg/kg/d; 2 males, 2 females), and negative control (saline [0.9% NaCl] solution; 5 males, 5 females). Serum biochemical and hematologic values were monitored. On necropsy examination, organ weights were determined, and histologic evaluation of tissue sections of liver, kidney, small intestine, testes, epididymis, and ovaries was performed. Hepatic and intestinal drug-metabolizing enzyme activities were measured, and relative amounts of CYP isoforms were determined by western blot analysis.

Results—The amount of a hepatic CYP2A-related isoform in dogs from the high-dose pentobarbital treatment group was twice that of dogs from the negative control group. CYP2C was not detectable in small intestinal mucosa of dogs from the negative control group; measurable amounts of CYP2C were found in dogs from the various (low-, mid-, and high-dose) pentobarbital treatment groups and from positive-pentobarbital and positive phenobarbital control groups. Several CYP-mediated reactions increased in a dosedependent manner. The lowest calculated effective dose of pentobarbital ranged from 200 to 450 µg/d.

Conclusions and Clinical Relevance—Several CYP isoforms and their associated reactions were induced in dogs by oral administration of low amounts of pentobarbital. (Am J Vet Res 2003;64:1167–1175)

Abstract

Objective—To determine the effect of oral administration of low doses of pentobarbital on cytochrome P450 (CYP) isoforms and CYP-mediated reactions in immature Beagles.

Animals—42 immature (12-week-old) Beagles.

Procedure—Dogs were grouped and treated orally as follows for 8 weeks: low-dose pentobarbital (50 µg/d; 4 males, 4 females), mid-dose pentobarbital (150 µg/d; 4 males, 4 females), high-dose pentobarbital (500 µg/d; 4 males, 4 females), positive-pentobarbital control (10 mg/kg/d; 2 males, 2 females), positivephenobarbital control (10 mg/kg/d; 2 males, 2 females), and negative control (saline [0.9% NaCl] solution; 5 males, 5 females). Serum biochemical and hematologic values were monitored. On necropsy examination, organ weights were determined, and histologic evaluation of tissue sections of liver, kidney, small intestine, testes, epididymis, and ovaries was performed. Hepatic and intestinal drug-metabolizing enzyme activities were measured, and relative amounts of CYP isoforms were determined by western blot analysis.

Results—The amount of a hepatic CYP2A-related isoform in dogs from the high-dose pentobarbital treatment group was twice that of dogs from the negative control group. CYP2C was not detectable in small intestinal mucosa of dogs from the negative control group; measurable amounts of CYP2C were found in dogs from the various (low-, mid-, and high-dose) pentobarbital treatment groups and from positive-pentobarbital and positive phenobarbital control groups. Several CYP-mediated reactions increased in a dosedependent manner. The lowest calculated effective dose of pentobarbital ranged from 200 to 450 µg/d.

Conclusions and Clinical Relevance—Several CYP isoforms and their associated reactions were induced in dogs by oral administration of low amounts of pentobarbital. (Am J Vet Res 2003;64:1167–1175)