New metabolic pathways of α-lipoic acid

被引:0
作者
Schupke, H
Hempel, R
Peter, G
Hermann, R
Wessel, K
Engel, J
Kronbach, T
机构
[1] Elbion AG, Dept Metab & Dev, D-01445 Radebeul, Germany
[2] ASTA Med Grp, Corp Res & Dev, Frankfurt, Germany
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中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The excretion and biotransformation of rac-alpha -lipoic acid (LA), which is used for the symptomatic treatment of diabetic polyneuropathy, were investigated following single oral dosing of [C-14]LA to mice (30 mg/kg), rats (30 mg/kg), dogs (10 mg/kg), and unlabeled LA to humans (600 mg). More than 80% of the radioactivity given was renally excreted, Metabolite profiles obtained by radiometric high-performance liquid chromatography revealed that LA was extensively metabolized irrespective of the species, Based on a new on-line liquid chromatography/tandem mass spectroscopy assay developed for negative ions, LA and a total of 12 metabolites were identified. Mitochondrial beta -oxidation played the paramount role in the metabolism of LA, Simultaneously, the circulating metabolites were subjected to reduction of the 1,2-dithiolane ring and subsequent S-methylation. In addition, evidence is given for the first time that the methyl sulfides formed were partly oxidized to give sulfoxides, predominantly in dogs, The disulfoxide of 2,4-bismethylmercapto-butanoic acid, the most polar metabolite identified, was the major metabolite in dogs, Furthermore, new data are presented that suggest conjugation with glycine occurred as a separate metabolic pathway in competition with P-oxidation, predominantly in mice.
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页码:855 / 862
页数:8
相关论文
共 23 条
[1]   Reduction of lipoic acid by lipoamide dehydrogenase [J].
Biewenga, GP ;
Dorstijn, MA ;
Verhagen, JV ;
Haenen, GRMM ;
Bast, A .
BIOCHEMICAL PHARMACOLOGY, 1996, 51 (03) :233-238
[2]   The pharmacology of the antioxidant lipoic acid [J].
Biewenga, GP ;
Haenen, GRMM ;
Bast, A .
GENERAL PHARMACOLOGY, 1997, 29 (03) :315-331
[3]   LIPOIC ACID FAVORS THIOLSULFINATE FORMATION AFTER HYPOCHLOROUS ACID SCAVENGING - A STUDY WITH LIPOIC ACID-DERIVATIVES [J].
BIEWENGA, GP ;
DEJONG, J ;
BAST, A .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1994, 312 (01) :114-120
[4]  
BIEWENGA GP, 1997, LIPOIC ACID PHARM ST, P137
[5]   REDUCTION AND TRANSPORT OF LIPOIC ACID BY HUMAN ERYTHROCYTES [J].
CONSTANTINESCU, A ;
PICK, U ;
HANDELMAN, GJ ;
HARAMAKI, N ;
HAN, D ;
PODDA, M ;
TRITSCHLER, HJ ;
PACKER, L .
BIOCHEMICAL PHARMACOLOGY, 1995, 50 (02) :253-261
[6]   LIPOATE METABOLISM IN PSEUDOMONAS-PUTIDA LP - THIOLSULFINATES OF LIPOATE AND BIS-NORLIPOATE [J].
FURR, HC ;
CHANG, HH ;
MCCORMICK, DB .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1978, 185 (02) :576-583
[7]  
Gregus Z, 1996, DRUG METAB DISPOS, V24, P682
[8]   ALPHA-LIPOIC ACID REDUCTION BY MAMMALIAN-CELLS TO THE DITHIOL FORM, AND RELEASE INTO THE CULTURE-MEDIUM [J].
HANDELMAN, GJ ;
HAN, D ;
TRITSCHLER, H ;
PACKER, L .
BIOCHEMICAL PHARMACOLOGY, 1994, 47 (10) :1725-1730
[9]   Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid [J].
Haramaki, N ;
Han, D ;
Handelman, GJ ;
Tritschler, HJ ;
Packer, L .
FREE RADICAL BIOLOGY AND MEDICINE, 1997, 22 (03) :535-542
[10]   METABOLISM OF DL-[1, 6-C-14]LIPOIC ACID IN RAT [J].
HARRISON, EH ;
MCCORMICK, DB .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1974, 160 (02) :514-522