Metabolic effects of pivalate in isolated rat hepatocytes

Ruff, Laura J.; Brass, Eric P.

doi:10.1016/s0041-008x(05)80012-2

Cited by 35 publications

(7 citation statements)

References 33 publications

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“…TMA-CoA is believed to be formed in vivo in rats because it is the obligatory intermediate for glycine and carnitine conjugates of TMA. Studies with TMA in hepatocytes provided direct evidence of the capability of jpet.aspetjournals.org rat liver cells to catalyze the formation of TMA-CoA thioester (Ruff and Brass, 1991). Consistent with the above-mentioned literature, TMA-CoA thioester was detected by HPLC analysis of liver extracts from TMA-pretreated rats (Fig.…”

Section: Discussionsupporting

confidence: 85%

In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

Li¹,

Grillo²,

Benet³

2003

J Pharmacol Exp Ther

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Two alternative metabolic pathways, acyl glucuronidation and acyl-CoA formation, are implicated in the generation of reactive acylating metabolites of carboxylic acids. Here, we describe studies that determine the relative importance of these two pathways in the metabolic activation of a model substrate, 2-phenylpropionic acid (2-PPA), in vivo in rats. Male SpragueDawley rats were pretreated with and without (Ϫ)-borneol (320 mg/kg i.p.), an inhibitor of acyl glucuronidation, or trimethylacetic acid (TMA, 500 mg/kg i.p.), an inhibitor of acyl-CoA formation, before receiving 2-PPA (racemic, 130 mg/kg). After administration of 2-PPA, livers were collected over a 2-h period and analyzed for 2-PPA acyl glucuronidation and 2-PPA-CoA formation by high-performance liquid chromatography. Covalent binding was measured by scintillation counting of washed liver protein precipitates. Results showed that pretreatment with TMA led to a 49% decrease in covalent binding of 2-PPA to liver proteins, when a 64% decrease in the exposure of 2-PPACoA was observed. Conversely, 95% inhibition of acyl glucuronidation by (Ϫ)-borneol, led to a 23% decrease in covalent binding to protein. These results suggest that metabolic activation by 2-PPA-CoA formation contributes to covalent adduct formation to protein in vivo to a greater extent than metabolic activation by acyl glucuronidation for this model substrate.

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Section: Discussionsupporting

confidence: 85%

In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

Li¹,

Grillo²,

Benet³

2003

J Pharmacol Exp Ther

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“…Short-chain carboxylates including acetate, propionate, butyrate, and the nonnatural substrate pivalate (trimethylacetate) use the early steps of the fatty acid oxidation pathway involving acyl-CoA and acyl-carnitine synthesis (7)(8)(9). Unlike acetate, however, pivalate cannot be oxidized to carbon dioxide in mammalian cells (10).…”

mentioning

confidence: 99%

Preclinical Evaluation of 3-¹⁸F-Fluoro-2,2-Dimethylpropionic Acid as an Imaging Agent for Tumor Detection

et al. 2014

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Deregulated cellular metabolism is a hallmark of many cancers. In addition to increased glycolytic flux, exploited for cancer imaging with 18 F-FDG, tumor cells display aberrant lipid metabolism. Pivalic acid is a short-chain, branched carboxylic acid used to increase oral bioavailability of prodrugs. After prodrug hydrolysis, pivalic acid undergoes intracellular metabolism via the fatty acid oxidation pathway. We have designed a new probe, 3-18 F-fluoro-2,2-dimethylpropionic acid, also called 18 F-fluoro-pivalic acid ( 18 F-FPIA), for the imaging of aberrant lipid metabolism and cancer detection. Methods: Cell intrinsic uptake of 18 F-FPIA was measured in murine EMT6 breast adenocarcinoma cells. In vivo dynamic imaging, time course biodistribution, and radiotracer stability testing were performed. 18 F-FPIA tumor retention was further compared in vivo to 18 F-FDG uptake in several xenograft models and inflammatory tissue. Results: 18 F-FPIA rapidly accumulated in EMT6 breast cancer cells, with retention of intracellular radioactivity predicted to occur via a putative 18 F-FPIA carnitine-ester. The radiotracer was metabolically stable to degradation in mice. In vivo imaging of implanted EMT6 murine and BT474 human breast adenocarcinoma cells by 18 F-FPIA PET showed rapid and extensive tumor localization, reaching 9.1% ± 0.5% and 7.6% ± 1.2% injected dose/g, respectively, at 60 min after injection. Substantial uptake in the cortex of the kidney was seen, with clearance primarily via urinary excretion. Regarding diagnostic utility, uptake of 18 F-FPIA was comparable to that of 18 F-FDG in EMT6 tumors but superior in the DU145 human prostate cancer model (54% higher uptake; P 5 0.002). Furthermore, compared with 18 F-FDG, 18 F-FPIA had lower normal-brain uptake resulting in a superior tumor-to-brain ratio (2.5 vs. 1.3 in subcutaneously implanted U87 human glioma tumors; P 5 0.001), predicting higher contrast for brain cancer imaging. Both radiotracers showed increased localization in inflammatory tissue. Conclusion: 18 F-FPIA shows promise as an imaging agent for cancer detection and warrants further investigation.

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“…A number of carboxylic acids may have direct toxicity after metabolism to the coenzyme A derivative, independent of any impact on carnitine homeostasis 34 . In vitro studies suggest that pivalate has only minimal toxicity at high concentrations independent of carnitine depletion, 7 and no unexplained toxicity has been demonstrated with pivalate prodrug use that would suggest an unrecognized toxicity of pivalate.…”

Section: Discussionmentioning

confidence: 99%

“…Although pivalate can undergo glucuronidation and then be excreted in the urine, 5 most of the absorbed pivalate in humans is excreted as pivaloylcarnitine in the urine 5 , 6 . The formation of pivaloylcarnitine is the result of pivalate activation to pivaloyl–coenzyme A, 7 with subsequent transfer of the pivaloyl moiety to carnitine to form pivaloylcarnitine 8 , 9 …”

mentioning

confidence: 99%

Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil

Brass

Mayer

Mulford

et al. 2003

Clinical Pharmacology & Therapeutics

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Metabolic effects of pivalate in isolated rat hepatocytes

Cited by 35 publications

References 33 publications

In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

Preclinical Evaluation of 3-¹⁸F-Fluoro-2,2-Dimethylpropionic Acid as an Imaging Agent for Tumor Detection

Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil

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Metabolic effects of pivalate in isolated rat hepatocytes

Cited by 35 publications

References 33 publications

In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

In Vivo Mechanistic Studies on the Metabolic Activation of 2-Phenylpropionic Acid in Rat

Preclinical Evaluation of 3-18F-Fluoro-2,2-Dimethylpropionic Acid as an Imaging Agent for Tumor Detection

Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil

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Preclinical Evaluation of 3-¹⁸F-Fluoro-2,2-Dimethylpropionic Acid as an Imaging Agent for Tumor Detection