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Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

Journal Article:

Abstract

Fibrate drugs are PPAR{alpha} agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPAR{alpha} agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey no. 2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study  More>>
Authors:
Aiming, Liu; Shuilin, Xie; [1]  He, Sun; [2]  Gonzalez, Frank J; [3]  Xiaoxiong, Wei; [4]  Dai Renke , E-mail: dai_renke@gibh.ac.cn [1] 
  1. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663 (China)
  2. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072 (China)
  3. National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)
  4. Medpace, Inc., Cincinnati, OH 45212 (United States)
Publication Date:
Mar 15, 2009
Product Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 235; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2008.12.015; PII: S0041-008X(08)00523-1; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; BLOOD; CREATINE; CREATININE; EOSIN; EXCRETION; HEMATOXYLIN; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROSCOPY; MONKEYS; MYOGLOBIN; NITROGEN; RECEPTORS; SODIUM; UREA
OSTI ID:
21182755
Country of Origin:
United States
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 0041-008X; TXAPA9; TRN: US09R1382057004
Availability:
Available from http://dx.doi.org/10.1016/j.taap.2008.12.015;INIS
Submitting Site:
INIS
Size:
page(s) 287-295
Announcement Date:
Jul 17, 2009

Journal Article:

Citation Formats

Aiming, Liu, Shuilin, Xie, He, Sun, Gonzalez, Frank J, Xiaoxiong, Wei, and Dai Renke , E-mail: dai_renke@gibh.ac.cn. Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties. United States: N. p., 2009. Web.
Aiming, Liu, Shuilin, Xie, He, Sun, Gonzalez, Frank J, Xiaoxiong, Wei, & Dai Renke , E-mail: dai_renke@gibh.ac.cn. Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties. United States.
Aiming, Liu, Shuilin, Xie, He, Sun, Gonzalez, Frank J, Xiaoxiong, Wei, and Dai Renke , E-mail: dai_renke@gibh.ac.cn. 2009. "Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties." United States.
@misc{etde_21182755,
title = {Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties}
author = {Aiming, Liu, Shuilin, Xie, He, Sun, Gonzalez, Frank J, Xiaoxiong, Wei, and Dai Renke , E-mail: dai_renke@gibh.ac.cn}
abstractNote = {Fibrate drugs are PPAR{alpha} agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPAR{alpha} agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey no. 2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity.}
journal = {Toxicology and Applied Pharmacology}
issue = {3}
volume = {235}
place = {United States}
year = {2009}
month = {Mar}
}