Antipyrine and caffeine dispositions in clinically normal dogs and dogs with progressive liver disease

Dawn Merton Boothe From the Departments of Veterinary Physiology and Pharmacology (Boothe), Statistics and Veterinary Anatomy and Public Health (Calvin), and Department of Veterinary Pathology (Green), The Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466; Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (Cullen); Office of the Dean, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803 (Jenkins); Worldwide Animal Health Clinical Research and Product Development, The Upjohn Co, Kalamazoo, MI 49001 (Brown); and USDA Agricultural Research Service, Food Animal Protection Research Laboratory, College Station, TX 77843 (Corrier).

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John Michael Cullen From the Departments of Veterinary Physiology and Pharmacology (Boothe), Statistics and Veterinary Anatomy and Public Health (Calvin), and Department of Veterinary Pathology (Green), The Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466; Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (Cullen); Office of the Dean, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803 (Jenkins); Worldwide Animal Health Clinical Research and Product Development, The Upjohn Co, Kalamazoo, MI 49001 (Brown); and USDA Agricultural Research Service, Food Animal Protection Research Laboratory, College Station, TX 77843 (Corrier).

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James Arthur Calvin From the Departments of Veterinary Physiology and Pharmacology (Boothe), Statistics and Veterinary Anatomy and Public Health (Calvin), and Department of Veterinary Pathology (Green), The Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466; Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (Cullen); Office of the Dean, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803 (Jenkins); Worldwide Animal Health Clinical Research and Product Development, The Upjohn Co, Kalamazoo, MI 49001 (Brown); and USDA Agricultural Research Service, Food Animal Protection Research Laboratory, College Station, TX 77843 (Corrier).

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William Louis Jenkins From the Departments of Veterinary Physiology and Pharmacology (Boothe), Statistics and Veterinary Anatomy and Public Health (Calvin), and Department of Veterinary Pathology (Green), The Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466; Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (Cullen); Office of the Dean, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803 (Jenkins); Worldwide Animal Health Clinical Research and Product Development, The Upjohn Co, Kalamazoo, MI 49001 (Brown); and USDA Agricultural Research Service, Food Animal Protection Research Laboratory, College Station, TX 77843 (Corrier).

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Scott Anthony Brown From the Departments of Veterinary Physiology and Pharmacology (Boothe), Statistics and Veterinary Anatomy and Public Health (Calvin), and Department of Veterinary Pathology (Green), The Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466; Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (Cullen); Office of the Dean, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803 (Jenkins); Worldwide Animal Health Clinical Research and Product Development, The Upjohn Co, Kalamazoo, MI 49001 (Brown); and USDA Agricultural Research Service, Food Animal Protection Research Laboratory, College Station, TX 77843 (Corrier).

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Robert Allan Green From the Departments of Veterinary Physiology and Pharmacology (Boothe), Statistics and Veterinary Anatomy and Public Health (Calvin), and Department of Veterinary Pathology (Green), The Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466; Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (Cullen); Office of the Dean, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803 (Jenkins); Worldwide Animal Health Clinical Research and Product Development, The Upjohn Co, Kalamazoo, MI 49001 (Brown); and USDA Agricultural Research Service, Food Animal Protection Research Laboratory, College Station, TX 77843 (Corrier).

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Donald Earl Carrier From the Departments of Veterinary Physiology and Pharmacology (Boothe), Statistics and Veterinary Anatomy and Public Health (Calvin), and Department of Veterinary Pathology (Green), The Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4466; Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (Cullen); Office of the Dean, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803 (Jenkins); Worldwide Animal Health Clinical Research and Product Development, The Upjohn Co, Kalamazoo, MI 49001 (Brown); and USDA Agricultural Research Service, Food Animal Protection Research Laboratory, College Station, TX 77843 (Corrier).

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Summary

Dispositions of caffeine and antipyrine were compared as indicators of decreasing hepatic function in dogs with experimentally induced progressive liver disease. Dimethylnitrosamine, a hepatospecific toxin, was administered orally to 16 dogs; 6 dogs served as controls (group 1). Three classes of liver disease were defined by histologic features: mild (group 2; n = 5), moderate (group 3; n = 6), and severe (group 4; n = 5). Disposition of antipyrine, and 24 hours later, caffeine was studied 3 weeks after the last dose of toxin in each dog. For both drugs, rapid IV administration of 20 mg/kg of body weight was administered and serum samples were obtained at intervals for determination of at least 5 terminal-phase drug half-lives. For both drugs, clearance and mean residence time differed among groups (P ≤ 0.01). Clearance of antipyrine and caffeine was decreased in groups 3 and 4, compared with groups 1 and 2. Antipyrine and caffeine mean residence times were longer in group-3 dogs, compared with dogs of groups 1 and 2. Correction of caffeine and antipyrine clearances for hepatic weight increased discrimination between groups 3 and 4. The clearance and mean residence time ratios of antipyrine to caffeine were calculated for each group and, when compared with values for group-1 dogs, were used to test for differences between the 2 drugs in response to disease. Ratios did not differ among groups. These results indicate that the disposition of antipyrine and caffeine may change similarly with progression of dimethylnitrosamine-induced liver disease.

Summary

Dispositions of caffeine and antipyrine were compared as indicators of decreasing hepatic function in dogs with experimentally induced progressive liver disease. Dimethylnitrosamine, a hepatospecific toxin, was administered orally to 16 dogs; 6 dogs served as controls (group 1). Three classes of liver disease were defined by histologic features: mild (group 2; n = 5), moderate (group 3; n = 6), and severe (group 4; n = 5). Disposition of antipyrine, and 24 hours later, caffeine was studied 3 weeks after the last dose of toxin in each dog. For both drugs, rapid IV administration of 20 mg/kg of body weight was administered and serum samples were obtained at intervals for determination of at least 5 terminal-phase drug half-lives. For both drugs, clearance and mean residence time differed among groups (P ≤ 0.01). Clearance of antipyrine and caffeine was decreased in groups 3 and 4, compared with groups 1 and 2. Antipyrine and caffeine mean residence times were longer in group-3 dogs, compared with dogs of groups 1 and 2. Correction of caffeine and antipyrine clearances for hepatic weight increased discrimination between groups 3 and 4. The clearance and mean residence time ratios of antipyrine to caffeine were calculated for each group and, when compared with values for group-1 dogs, were used to test for differences between the 2 drugs in response to disease. Ratios did not differ among groups. These results indicate that the disposition of antipyrine and caffeine may change similarly with progression of dimethylnitrosamine-induced liver disease.

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