Effects of Long‐Term Phenobarbital Treatment on the Liver in Dogs

Abstract

Long-term administration of phenobarbital has been reported to cause hepatic injury in dogs. Phenobarbital induces hepatic enzymes, and it may be difficult to distinguish the effect of enzyme induction on serum liver enzyme activities from actual hepatic damage. The hepatotoxicity of phenobarbital and the impact of enzyme induction on serum liver enzyme activity were investigated prospectively in 12 normal dogs. Phenobarbital was administered for 29 weeks at 5 mg per kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h, resulting in therapeutic serum phenobarbital concentrations (20-40 microg/mL). Serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), fasted bile acids (fBA), total bilirubin, and albumin were determined before and during treatment. Lateral abdominal radiographs, abdominal ultrasounds, and histopathologic examinations of liver tissue obtained by ultrasound-guided biopsy were performed before and during treatment. Radiographs revealed a moderate increase in liver size in most dogs. Ultrasonographic examination revealed no change in liver echogenicity or architecture. No evidence of morphologic liver damage was observed histopathologically. ALP and ALT increased significantly (P < .05), GGT increased transiently, and albumin decreased transiently during the study. There were no significant changes in AST, bilirubin, and fBA. These results suggest that increases in serum ALP, ALT, and GGT may reflect enzyme induction rather than hepatic injury during phenobarbital treatment in dogs. Serum AST, fBA, and bilirubin, and ultrasonographic evaluation of the liver are not affected by the enzyme-inducing effect of phenobarbital and can therefore be helpful to assess liver disease in dogs treated with the drug.

Biochemical changes in the blood serum of dogs treated with phenobarbital

“…A transient statistically significant increase in albumin and total protein concentration during epilepsy treatment with phenobarbitone in a dose of 10 mg/kg/day for 27 weeks was reported by Müller et al (2000). Similar results were obtained in a study on 95 dogs treated with phenobarbitone doses in a range from less than 2 mg/kg/day up to over 10 mg/kg/day (Aitken et al, 2003).…”

“…A number of authors states that phenobarbitone application in dogs results in increased serum AP and ALT activities which are not accompanied by clinical signs of liver disease (Fanuel-Barret and Vivier, 1993; Chauvet et al, 1995;Center, 1995;Booth, 1996;Dowling, 1999;Müller et al, 2000;Foster et al, 2001;Aitken et al, 2003). In support of this finding are the results of our study with the difference that in the group of dogs suffering from idiopathic epilepsy after treatment with 16 mg/kg/day phenobarbitone two dogs had clinical symptoms of hepatotoxicity.…”

“…AST can increase as a result of phenobarbitone treatment in humans (Verma and Haidukewych, 1994) and rats (Attia and Aref, 1991). Despite the fact that increased AST activity caused by increased enzyme induction in dogs is possible (center, 1995) a study on Beagle dogs treated with high phenobarbitone doses for over 3 weeks (Tettenborn et al, 1973) and a study on 12 dogs of different breeds treated with 5 mg/kg/day for 27 weeks did not confirm this hypothesis (Müller et al, 2000).…”

“…A number of studies carried out on dogs (Dayrell-Hart et al, 1991;Chauvet et al, 1995;Foster et al, 2000;Müller et al, 2000;Aitken et al, 2003;Gaskill et al, 2004;Gaskill et al, 2005) report increased activities of alanine transaminase (ALT) and alkaline phosphatase (AP). Increased ALT and AP activities were mainly recorded in patients who did not display clinical signs of hepatopaties.…”

A Toxicologist's Guide to the Preclinical Assessment of Hepatic Microsomal Enzyme Induction

“…In a longterm study (29 weeks) on the effects of phenobarbital in dogs, serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) increased significantly, GGT increased transiently, and albumen decreased transiently during the study in the absence of any histopathological damage to the liver (Muller et al 2000). A single i.p.…”