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

Rikki L. Fitzpatrick, Jessica M. Quimby, Kellyi K. Benson, Dominique Ramirez, Liberty G. Sieberg, Luke Anthony Wittenburg, Daniel L. Gustafson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalJournal of Veterinary Internal Medicine
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

liver diseases
pharmacokinetics
Liver Diseases
Cats
Pharmacokinetics
cats
half life
Half-Life
liver microsomes
mirtazapine
In Vitro Techniques
Liver Microsomes
microsomes
bilirubin
Microsomes
Tandem Mass Spectrometry
case-control studies
Serum
Bilirubin
Liquid Chromatography

Keywords

  • appetite stimulant
  • feline
  • hepatic
  • microsomes

ASJC Scopus subject areas

  • veterinary(all)

Cite this

Fitzpatrick, R. L., Quimby, J. M., Benson, K. K., Ramirez, D., Sieberg, L. G., Wittenburg, L. A., & Gustafson, D. L. (Accepted/In press). In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease. Journal of Veterinary Internal Medicine. https://doi.org/10.1111/jvim.15237

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 Anthony; Gustafson, Daniel L.

In: Journal of Veterinary Internal Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Fitzpatrick, Rikki L. ; Quimby, Jessica M. ; Benson, Kellyi K. ; Ramirez, Dominique ; Sieberg, Liberty G. ; Wittenburg, Luke Anthony ; Gustafson, Daniel L. / In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease. In: Journal of Veterinary Internal Medicine. 2018.
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abstract = "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.",
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AU - Fitzpatrick, Rikki L.

AU - Quimby, Jessica M.

AU - Benson, Kellyi K.

AU - Ramirez, Dominique

AU - Sieberg, Liberty G.

AU - Wittenburg, Luke Anthony

AU - Gustafson, Daniel L.

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AB - 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.

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