title: Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic-adipic aciduria in beagle dogs.
abstract: Ibipinabant (IBI), a potent cannabinoid-1 receptor (CB1R) antagonist, previously in development for the treatment of obesity, causes skeletal and cardiac myopathy in beagle dogs. This toxicity was characterized by increases in muscle-derived enzyme activity in serum and microscopic striated muscle degeneration and accumulation of lipid droplets in myofibers. Additional changes in serum chemistry included decreases in glucose and increases in non-esterified fatty acids and cholesterol, and metabolic acidosis, consistent with disturbances in lipid and carbohydrate metabolism. No evidence of CB1R expression was detected in dog striated muscle as assessed by polymerase chain reaction, immunohistochemistry, Western blot analysis, and competitive radioligand binding. Investigative studies utilized metabonomic technology and demonstrated changes in several intermediates and metabolites of fatty acid metabolism including plasma acylcarnitines and urinary ethylmalonate, methylsuccinate, adipate, suberate, hexanoylglycine, sarcosine, dimethylglycine, isovalerylglycine, and 2-hydroxyglutarate. These results indicated that the toxic effect of IBI on striated muscle in beagle dogs is consistent with an inhibition of the mitochondrial flavin-containing enzymes including dimethyl glycine, sarcosine, isovaleryl-CoA, 2-hydroxyglutarate, and multiple acyl-CoA (short, medium, long, and very long chain) dehydrogenases. All of these enzymes converge at the level of electron transfer flavoprotein (ETF) and ETF oxidoreductase. Urinary ethylmalonate was shown to be a biomarker of IBI-induced striated muscle toxicity in dogs and could provide the ability to monitor potential IBI-induced toxic myopathy in humans. We propose that IBI-induced toxic myopathy in beagle dogs is not caused by direct antagonism of CB1R and could represent a model of ethylmalonic-adipic aciduria in humans.
authors: Drug Safety Evaluation and Pharmaceutical Candidate Optimization, Research Division, Bristol-Myers Squibb Co., Princeton, New Jersey 08543, USA. lindsay.tomlinson@pfizer.com
authors: Lindsay
authors: L
authors: Tomlinson
authors: Mark A
authors: MA
authors: Tirmenstein
authors: Evan B
authors: EB
authors: Janovitz
authors: Nelly
authors: N
authors: Aranibar
authors: Karl-Heinz
authors: KH
authors: Ott
authors: John C
authors: JC
authors: Kozlosky
authors: Laura M
authors: LM
authors: Patrone
authors: William E
authors: WE
authors: Achanzar
authors: Karen A
authors: KA
authors: Augustine
authors: Kimberly C
authors: KC
authors: Brannen
authors: Kenneth E
authors: KE
authors: Carlson
authors: Jeffrey H
authors: JH
authors: Charlap
authors: Katherine M
authors: KM
authors: Dubrow
authors: Liya
authors: L
authors: Kang
authors: Laura T
authors: LT
authors: Rosini
authors: Julieta M
authors: JM
authors: Panzica-Kelly
authors: Oliver P
authors: OP
authors: Flint
authors: Frederic J
authors: FJ
authors: Moulin
authors: John R
authors: JR
authors: Megill
authors: Haiying
authors: H
authors: Zhang
authors: Michael J
authors: MJ
authors: Bennett
authors: Joseph J
authors: JJ
authors: Horvath
mesh_terms: D000272:Adipates / Q000652:urine*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002331:Carnitine / Q000097:blood; D017931:DNA Primers; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D008314:Malonates / Q000652:urine*; D055432:Metabolomics; D018482:Muscle, Skeletal / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000272:Adipates; D017931:DNA Primers; D008314:Malonates; D043884:Receptor, Cannabinoid, CB1; C038080:ethylmalonic acid; D002331:Carnitine