Hepatic toxicity of dronedarone in mice: role of mitochondrial β-oxidation.

Dronedarone is an amiodarone-like antiarrhythmic drug associated with severe liver injury. Since dronedarone inhibits mitochondrial respiration and β-oxidation in vitro, mitochondrial toxicity may also explain dronedarone-associated hepatotoxicity in vivo. We therefore studied hepatotoxicity of dronedarone (200mg/kg/day for 2 weeks or 400mg/kg/day for 1 week by intragastric gavage) in heterozygous juvenile visceral steatosis (jvs(+/-)) and wild-type mice.

Effect of carnitine, acetyl-, and propionylcarnitine supplementation on the body carnitine pool, skeletal muscle composition, and physical performance in mice.

Purpose: Pharmacokinetics and effects on skeletal muscle and physical performance of oral acetylcarnitine and propionylcarnitine are not well characterized. We therefore investigated the influence of oral acetylcarnitine, propionylcarnitine, and carnitine on body carnitine homeostasis, energy metabolism, and physical performance in mice and compared the findings to non-supplemented control animals.

Methods: Mice were supplemented orally with 2 mmol/kg/day carnitine, acetylcarnitine, or propionylcarnitine for 4 weeks and studied either at rest or after exhaustive exercise.

Quantification of plasma carnitine and acylcarnitines by high-performance liquid chromatography-tandem mass spectrometry using online solid-phase extraction.

Carnitine is an amino acid derivative that plays a key role in energy metabolism. Endogenous carnitine is found in its free form or esterified with acyl groups of several chain lengths. Quantification of carnitine and acylcarnitines is of particular interest for screening for research and metabolic disorders.

Determination of free and total valproic acid in human plasma by capillary electrophoresis with contactless conductivity detection.

A new approach for the determination of free and total valproic acid in small samples of 140 μL human plasma based on capillary electrophoresis with contactless conductivity detection is proposed. A dispersive liquid-liquid microextraction technique was employed in order to remove biological matrices prior to instrumental analysis. The free valproic acid was determined by isolating free valproic acid from protein-bound valproic acid by ultrafiltration under centrifugation of 100 μL sample.

Effect of short- and long-term treatment with valproate on carnitine homeostasis in humans.

Aims: The aim of this study was to identify the mechanisms of hypocarnitinemia in patients treated with valproate.

Methods: Plasma concentrations and urinary excretion of carnitine, acetylcarnitine, propionylcarnitine, valproylcarnitine, and butyrobetaine were determined in a patient starting valproate treatment and in 10 patients on long-term valproate treatment. Transport of carnitine and valproylcarnitine by the proximal tubular carnitine transporter OCTN2 was assessed in vitro.

Determination of creatine and phosphocreatine in muscle biopsy samples by capillary electrophoresis with contactless conductivity detection.

A capillary electrophoresis method with contactless conductivity detection was evaluated as a new approach for quantification of creatine and phosphocreatine in human quadriceps femoris biopsy samples. The running buffers employed consisted of 1 M acetic acid at a pH of 2.3 for the determination of creatine and 50 mM 3-(N-morpholino)propanesulfonic acid/30 mM histidine at a pH of 6.

Capillary electrophoresis with contactless conductivity detection for the determination of carnitine and acylcarnitines in clinical samples.

A capillary electrophoresis method with contactless conductivity detection was developed for the quantification of carnitine and six acylcarnitines in plasma and urine samples. The running buffer employed consisted of 500 mmol/L acetic acid, 1.0 mmol/L hydroxypropyl-β-cyclodextrin and 0.

Quantification of plasma lactate concentrations using capillary electrophoresis with contactless conductivity detection.

The quantification of plasma lactate and evaluation of the lactate threshold by CE with capacitively coupled contactless conductivity is demonstrated. The only sample preparation needed was deproteinization with a ACN/methanol mixture. A solution of 10 mmol/L 2-morpholinoethanesulfonic acid monohydrate, 10 mmol/L DL-histidine, 70 μmol/L hexadecyltrimethylammonium bromide, pH 6.

The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells.

Amiodarone is a class III antiarrhythmic drug with potentially life-threatening hepatotoxicity. Recent in vitro investigations suggested that the mono-N-desethyl (MDEA) and di-N-desethyl (DDEA) metabolites may cause amiodarone's hepatotoxicity. Since cytochrome P450 (CYP) 3A4 is responsible for amiodarone N-deethylation, CYP3A4 induction may represent a risk factor.