Pharmacokinetics and metabolism of idebenone in healthy male subjects

Bodmer, Michael; Vankan, Pierre; Dreier, Manfred; Kutz, K; Drewe, Jürgen

doi:10.1007/s00228-008-0596-1

Cited by 46 publications

(41 citation statements)

References 25 publications

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“…In fact, NF-κB activation is induced by several inflammatory mediators, such as IL-1β, TNFα, and metalloproteinases, all molecules found elevated in DMD [57,[98][99][100][101][102]. Active NF-κB is able to translocate to the nucleus, inducing the expression of genes encoding for cytokines and chemokines, cell adhesion molecules, and matrix metalloproteinases [103][104][105][106][107].…”

Section: Crosstalk Between Oxidative Stress and Inflammatory Responsementioning

confidence: 99%

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Forcina

Pelosi

Miano

et al. 2017

JFMK

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Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which the dystrophin gene is mutated, resulting in dysfunctional dystrophin protein. Without dystrophin, the dystrophin-glycoprotein complex (DGC) is unstable, leading to an increase in muscle damage. Moreover, the imbalance between muscle damage and repair leads to a chronic inflammatory response and an increase in the amount of fibrosis over time. The absence of dystrophin at the sarcolemma also delocalizes and downregulates nitric oxide synthase (nNOS) and alters enzymatic antioxidant responses, leading to an increase in oxidative stress. In this review, we analyze the pathogenic role of both inflammation and oxidative stress in muscular dystrophy.

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Section: Crosstalk Between Oxidative Stress and Inflammatory Responsementioning

confidence: 99%

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Forcina

Pelosi

Miano

et al. 2017

JFMK

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“…Study SNT-I-002 and SNT-I-004 were single-group studies in which healthy male subjects received one dose of idebenone after intake of a continental breakfast; study SNT-I-001 was a parallel-group, cross-over study of two dose levels of idebenone (150 mg and 750 mg) in which subjects received a single dose of idebenone once after fasting and once after a meal; study SNT-I-003 was a parallel-group study in which subjects received first a single oral dose of idebenone, followed after a 7-day washout period by repeated doses three times daily (tid) at 8-hour intervals for 14 days. The repeated-dose study was recently published [10]. The morning dose was given after intake of a continental breakfast.…”

Section: ■ Study Designmentioning

confidence: 99%

“…For this reason, the goals of the present clinical pharmacology program were to assess more accurately the pharmacokinetics and metabolism of idebenone (parent drug and metabolites) and to evaluate the safety of idebenone, administered as single oral doses of up to 1050 mg under fasted and fed conditions, and of up to 2250 mg daily for 2 weeks, in healthy male subjects [10].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic properties and metabolism of idebenone

2009

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Four phase 1 studies were conducted to assess the pharmacokinetics and metabolism of idebenone (including parent drug and inactive metabolites QS10, QS6, and QS4) and to evaluate the safety of a wide range of idebenone doses and regimens in healthy adult men. After a single oral dose of idebenone 150 mg, 750 mg, or 1050 mg in fasted or fed subjects, blood samples were taken for up to 72 hours. In one study, after a single oral dose and a 7-day washout period, subjects received repeated doses of idebenone 150 mg or 750 mg every 8 hours for 14 days. In the repeated-dose study, urine samples also were taken. Plasma and urine samples were analysed with the use of liquid chromatography with tandem mass spectrometry. Non-compartmental standard pharmacokinetic methods were used. In these studies, a total of 69 subjects ranging in age from 19 to 41 years (body weight, 57-94.6 kg) were included. Plasma concentrations of parent idebenone were low but increased in proportion to dose and increased approximately five-fold in the presence of food. Total QS4 was the main metabolite in plasma and urine. The most common adverse events were loose stool, fatigue, headache, and disturbances in attention. Idebenone was well tolerated in single oral doses up to 1050 mg and in repeated daily doses up to 2250 mg. Idebenone showed linear pharmacokinetics after single and repeated oral dosing. Administration after a meal resulted in the highest exposure to parent idebenone.

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“…Administered idebenone in human is metabolized by oxidative shortening of the 10-hydroxydecyl side chain, and reduction of the quinone ring and subsequent conjugation yielding the sulfates and glucuronides of the hydroquinone derivatives of the parent compound and the oxidized metabolites. 34,35) The total idebenone, which is the sum of parent idebenone and deconjugated idebenone by the acid treatment, in human blood was determined in this study. Idebenone was not detected, and an unknown peak of other fluorescent substances was detected, as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Determination of Idebenone in Plasma by HPLC with Post-Column Fluorescence Derivatization Using 2-Cyanoacetamide

Nohara

Suzuki

Yamazaki

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Idebenone is a benzoquinone analog that is used in the treatment of several neurological disorders including Friedreich's ataxia. It was found that the reaction of idebenone with 2-cyanoacetamide under alkaline conditions generates fluorescent products, and the reaction was considered to proceed via Craven's reaction. The reaction mixture from idebenone gave fluorescence with excitation and emission maximum wavelengths at 358 nm and 409 nm, respectively. It was adopted for HPLC with post-column fluorescence derivatization of idebenone. Idebenone in the plasma showed a linear response in the range of 0.5-32 ng (25-1600 ng/mL), and the quantitation limit (S/N 10) was 12.5 ng/mL. The detection limit (S/N 3) of the standard solution of idebenone was 0.1 ng. The HPLC system was applied to the human blood plasma obtained by finger prick. The plasma sample obtained by finger prick gave a similar chromatogram to that of venous blood obtained by venipuncture.Key words idebenone; finger prick; 2-cyanoacetamide; fluorescence derivatization; HPLC Idebenone is a synthetic analog of ubiquinone, 1) which is an essential component of the mitochondrial respiratory chain responsible for oxidative phosphorylation, and may prevent oxidative damage in the human body as an antioxidant. 2,3)Idebenone also has potent antioxidant activity and facilitates the flux of electrons along the mitochondrial electron transport chain, increasing the production of ATP, and has already been clinically investigated for the treatment of several neurological disorders, which include Friedreich's ataxia and Leber's hereditary optic neuropathy. 4,5) The pharmacokinetic properties of idebenone have been investigated by HPLC. Several procedures have been developed to analyze idebenone in biological samples by HPLC coupled with UV, electrochemical, or mass spectrometry detection. [6][7][8][9] HPLC methods employing mass spectrometry and electrochemical detectors have higher selectivity and sensitivity than those with a UV detector; however, these methods are not available in many laboratories because of a lack of specialized equipment. HPLC coupled with a fluorophotometric detector has been widely used in the determination of various substances in biological samples because of its high sensitivity and selectivity. However, idebenone needs fluorescence derivatization for the development of fluorimetric detection because it is not a fluorescent substance itself. 2-Cyanoacetamide has been used as a post-column derivatization reagent of fluorimetric HPLC for catecholamines, 3,4-dihydroxyphenylalanine, unsaturated disaccharides, and benzoquinones. [10][11][12][13][14][15] In the present study, 2-cyanoacetamide was tested for the fluorophotometric reagent of idebenone because idebenone is a benzoquinone compound. It was found that idebenone reacted with 2-cyanoacetamide under alkaline conditions with heating to form fluorescent products. This reaction was applied to HPLC with post-column fluorescence derivatization of idebenone.The salting out effect is useful a...

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Pharmacokinetics and metabolism of idebenone in healthy male subjects

Abstract: Idebenone exhibited dose-dependent pharmacokinetics in daily doses up to 2,250 mg. In 6/14 subjects, adverse events of mild to moderate severity were observed.

Cited by 46 publications

References 25 publications

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Pharmacokinetic properties and metabolism of idebenone

Determination of Idebenone in Plasma by HPLC with Post-Column Fluorescence Derivatization Using 2-Cyanoacetamide

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