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In Vivo and in Vitro Assessment of Mirtazapine Pharmacokinetics in Cats with Liver Disease

Fitzpatrick RL, Quimby JM, Benson KK, Ramirez D, Sieberg LG, et al. In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease. J Vet Intern Med. 2018 Nov;32(6):1951-1957. 

Mirtazapine is a commonly used appetite stimulant in feline medicine. It is used in a wide variety of conditions to encourage increased food intake with significant efficacy. It is known that renal disease decreases the clearance of mirtazapine in cats, but the effects of liver disease are unknown. In humans, liver disease may increase the half-life of this drug. The purpose of this study was to determine the effects of liver disease on the half-life of mirtazapine in cats.

This study was designed as a prospective trial comparing the metabolism of mirtazapine in cats with liver disease against healthy age matched controls. Data was also collected from liver microsomes for in-vitro analysis. Cats were diagnosed with liver disease based on elevated ALT and/or bilirubin. Cats could not have concurrent kidney disease or hyperthyroidism. Age matched controls were within 1 year of the liver disease cat, and had a normal CBC, biochemistry, UA, and T4.

Eleven cats were included in each group. In the liver disease group there were 5 females and 6 males with an average age of 8.8 years. Controls were 8 females and 3 males with an average age of 8.3 years. Each cat was administered 1.88mg mirtazapine orally and serum was collected at 1, 4, and 24h post collection and mirtazapine concentration assessed.

Liver microsomes were isolated post-mortem from 3 cats with liver disease (hepatic lipidosis) and 4 cats with normal liver function. All cats were euthanized for reasons unrelated to the study.  After isolation of liver microsomes, they were incubated with a known concentration of mirtazapine for 80 minutes and the loss of mirtazapine measured.

For the in-vivo component of this study, a 185% increase in mirtazapine half-life was seen in cats with liver disease. Cats with liver disease also had prolonged time to maximal serum concentration. The in-vitro component showed a half-life of 313.6 minutes in cats with liver disease, compared with 37.5 minutes for cats without. Both the in vivo and in vitro findings support a decreased metabolism and increased half-life of mirtazapine in cats with liver disease.

Some drawbacks to this study exist. The authors did not differentiate between types of liver disease, nor did they account for severity of disease. The effects of chronic dosing were not investigated, only a point dose. Finally, a limited sampling methodology was used, and more time points may have been beneficial.

The authors suggest that, in cats with liver disease, mirtazapine may need to be dosed at a longer interval than usual. While a 24h dosing schedule is used in most cats, 48 or even 72h dosing may be preferred in cats with liver disease. (MRK)

See Also

Agnew W, Korman R. Pharmacological appetite stimulation: rational choices in the inappetent cat. J Feline Med Surg. 2014;16:749–756.

Quimby JM, Gustafson DL, Lunn KF. The pharmacokinetics of mirtazapine in cats with chronic kidney disease and in age-matched control cats. J Vet Intern Med. 2011;25:985–989.

Quimby JM, Gustafson DL, Samber BJ, et al. Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats. J Vet Pharmacol Ther. 2011;34:388–396.