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In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease

Fitzpatrick, Rikki L., Quimby, Jessica M., Benson, Kellyi K., Ramirez, Dominique, Sieberg, Liberty G., Wittenburg, Luke A., Gustafson, Daniel L.
Journal of veterinary internal medicine 2018 v.32 no.6 pp. 1951-1957
alanine transaminase, alkaline phosphatase, bilirubin, blood serum, case-control studies, cats, drugs, half life, humans, in vitro studies, liquid chromatography, liver diseases, liver microsomes, models, oral administration, pharmacokinetics, tandem mass spectrometry
BACKGROUND: Liver disease (LD) prolongs mirtazapine half‐life in humans, but it is unknown if this occurs in cats with LD and healthy cats. HYPOTHESIS/OBJECTIVES: To determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats. ANIMALS: Eleven LD and 11 age‐matched control cats. METHODS: Case‐control study. Serum was obtained 1 and 4 hours (22 cats) and 24 hours (14 cats) after oral administration of 1.88 mg mirtazapine. Mirtazapine concentrations were measured by liquid chromatography with tandem mass spectrometry. Drug exposure and half‐life were predicted using limited sampling modeling and estimated using noncompartmental methods. in vitro mirtazapine pharmacokinetics were assessed using liver microsomes from 3 LD cats and 4 cats without LD. RESULTS: There was a significant difference in time to maximum serum concentration between LD cats and control cats (median [range]: 4 [1‐4] hours versus 1 [1‐4] hours; P = .03). The calculated half‐life of LD cats was significantly prolonged compared to controls (median [range]: 13.8 [7.9‐61.4] hours versus 7.4 [6.7‐9.1] hours; P < .002). Mirtazapine half‐life was correlated with ALT (P = .002; r = .76), ALP (P < .0001; r = .89), and total bilirubin (P = .0008; r = .81). The rate of loss of mirtazapine was significantly different between microsomes of LD cats (–0.0022 min⁻¹, CI: −0.0050 to 0.00054 min⁻¹) and cats without LD (0.01849 min⁻¹, CI: −0.025 to −0.012 min⁻¹; P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with LD might require less frequent administration of mirtazapine than normal cats.