Chronic Effects of Flutamide in Male Beagle Dogs

Frank, Doyle; Sharpe, Neal; Scott, Mary Celine; Mirro, Elmer J.; Hartman, Barbara; Halliwell, W. H.

doi:10.1080/101926230490274416

Cited by 2 publications

(2 citation statements)

References 18 publications

(17 reference statements)

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“…Treatment of dogs for 2, 3, and 4 years with flutamide up to 40 mg/kg daily resulted in a slight increase in ALT (up to 135%) and alkaline phosphatase activities (up to 125%). Histopathologic findings included centrilobular hepatocyte pigmentation, cytoplasmaic vacuolation, hepatic bile duct proliferation, and excessive mucus in gallbladder (29). Bicalutamide, which is another nonsteroidal antiandrogen and chemical analog of flutamide, produced no liver findings in preclinical toxicology studies in rats treated with bicalutamide up to 500 mg/kg for 1 month or up to 75 mg/kg for 12 months (30).…”

Section: Discussionmentioning

confidence: 99%

Transport, Metabolism, and Hepatotoxicity of Flutamide, Drug–Drug Interaction with Acetaminophen Involving Phase I and Phase II Metabolites

Kostrubsky

Strom

Ellis

et al. 2007

Chem. Res. Toxicol.

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Treatment with flutamide has been associated with clinical hepatotoxicty. The toxicity, metabolism,and transport of flutamide were investigated using cultured human hepatocytes. Flutamide and its major metabolite, 2-hydroxyflutamide, caused an inhibition of taurocholate efflux in human hepatocytes with an IC50=75 microM and 110 microM, respectively. Treatment of hepatocytes with flutamide or 2-hydroxyflutamide for 24 h resulted in time- and concentration-dependent toxicity as assessed by inhibition of protein synthesis. Toxicity was greater after 1 h than after 24 h of treatment. Recovery in inhibition of protein synthesis by 24 h was attributed to the decreased presence of flutamide due to its metabolism. Flutamide was metabolized by hepatocytes to several metabolites, and formation of reactive intermediates of flutamide, as evidenced by the presence of glutathione-related adducts, was observed. Inhibition of flutamide metabolism by 1-aminobenzotriazole (ABT) resulted in enhancement of flutamide toxicity, which was associated with sustained levels of nonmetabolized drug. ABT also prevented the formation of reactive intermediates of flutamide. There was an additive toxicity when cells were treated with a combination of flutamide and 2-hydroxyflutamide. Simultaneous treatment with flutamide and acetaminophen (APAP) resulted in additive to synergistic toxic effects. Flutamide and APAP were found to have significant effects on each other's metabolism. Flutamide inhibited glucuronidation and sulfation of APAP, resulting in greater amounts of APAP available for bioactivation. APAP inhibited the hydroxylation of flutamide, and subsequent sulfation and acetylation of 4-nitro-3-(trifluoromethyl) aniline, a metabolite of flutamide. In summary, we suggest that inhibition of bile acid efflux by flutamide and its 2-hydroxy metabolite may play a role in flutamide-induced liver injury. Both flutamide and 2-hydroxyflutamide are responsible for cytotoxicity if not metabolized. The data also suggest a possible drug-drug interaction between flutamide and APAP, resulting in inhibition of flutamide metabolism and increased APAP bioactivation and toxicity.

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Section: Discussionmentioning

confidence: 99%

Transport, Metabolism, and Hepatotoxicity of Flutamide, Drug–Drug Interaction with Acetaminophen Involving Phase I and Phase II Metabolites

Kostrubsky

Strom

Ellis

et al. 2007

Chem. Res. Toxicol.

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“…Nonsteroidal antiandrogen flutamide administered at 5 mg/kg/day per os for 1 year did not alter libido or sperm production in dogs (Romagnoli, 2006). However, longer administration of flutamide for two or more years caused testicular interstitial cell hyperplasia, seminiferous tubular atrophy and degeneration (Frank et al, 2004). Flutamide is not approved for use in veterinary medicine.…”

Section: Hormones and Anti‐hormonal Agentsmentioning

confidence: 99%

Effect of drugs on fertility in male dogs: A review

Zduńczyk

Domosławska

2022

Reprod Domestic Animals

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The aim of this literature review was to present and discuss the available data on the positive and negative effects of drugs on male dog fertility. Apart from information on hormones and anti‐hormonal agents, there is still only little information available regarding the effect of other drugs on sexual function and fertility in male dogs. A negative impact on fertility in male dogs has been reported for vincristine, cyclophosphamide, tetracycline and ketoconazole. However, preclinical safety studies of drugs for human use indicated that spermatogenesis in dogs may be sensitive to a wide variety of drugs. Thus, potential adverse effects of drugs on fertility should always be considered before their use in stud dogs. Also, in cases of reduced fertility or infertility in male dogs, previous medical treatment should be taken into account as a possible cause. In most cases, the effects of drugs on sexual function and spermatogenesis are reversible after the discontinuation of the drug. Further studies on the effects of drugs on male dog fertility are needed.

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Chronic Effects of Flutamide in Male Beagle Dogs

Cited by 2 publications

References 18 publications

Transport, Metabolism, and Hepatotoxicity of Flutamide, Drug–Drug Interaction with Acetaminophen Involving Phase I and Phase II Metabolites

Transport, Metabolism, and Hepatotoxicity of Flutamide, Drug–Drug Interaction with Acetaminophen Involving Phase I and Phase II Metabolites

Effect of drugs on fertility in male dogs: A review

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