gamma-Hydroxybutyrate (chemical formula HOOC-CH2-CH2- CH2OH) is a four-carbon molecule that is found naturally in the central nervous system and, in higher concentrations, in peripheral tissues. It has a structure much like gamma-aminobutyric acid (GABA), which is better understood than GHB and acts as an inhibitory neurotransmitter in vivo. gamma-Aminobutyric acid is catabolized by transamination to succinate semialdehyde, which is then oxidized to succinate. Brain tissue is capable of reducing succinate semialdehyde to GHB. Concentrations of both GHB and GHB-oxidizing enzymes are 15 to 20 times higher in kidney, heart, skeletal muscle, and brown fat than in the central nervous system.
Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyses the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyzes the conversion to succinic semialdehyde in the presence of alpha-ketoglutarate. An alternate pathway of biotransformation involves beta-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified. /Sodium oxybate/
In preregistration clinical trials, serum enzyme elevations were reported in small numbers of treated patients, but no instance of clinically apparent liver injury was reported. Since the approval and more widespread use of oxybate, there have been no published cases of liver injury due to oxybate, and in postmarketing overviews of adverse events hepatotoxicity was not listed. Thus, despite use in high doses (3 to 9 g daily), acute liver injury from oxybate must be very rare, if it occurs at all.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. Fecal and renal excretion is negligible. 5% renal elimination.
apparent oral cl=9.1 mL/min/kg [healthy adults receiving a single oral dose of 25 mg/kg]
4.5 mL/min/kg [cirrhotic patients without ascites receiving a single oral dose of 25 mg/kg]
4.1 mL/min/kg [cirrhotic patients with ascites receiving a single oral dose of 25 mg/kg]
Gamma-hydroxybutyric acid (GHB) ... absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg/kg The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentrations normalized to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased. These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range. The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.
After ingestion, GHB is rapidly absorbed and quickly crosses the blood-brain barrier. It is not protein bound and is rapidly metabolized and excreted through the lungs. It has specific binding sites and selective brain distribution with the highest concentration in the basal ganglia.
Reaction ofγ-Hydroxy-N-[1-(dimethylcarbamoyl)ethyl]butanamides under the ‘Direct Amide Cyclization’ Conditions
作者：Boyan Iliev、Anthony Linden、Heinz Heimgartner
DOI：10.1002/hlca.200690008
日期：2006.1
the imino lactones was achieved by increasing the substitution in the five-membered ring, and their structure, in the form of the hydrochlorides, was established independently by X-raycrystallography (Fig. 4). A derivative 15 of the imino lactone 12a was prepared by the reaction with the 2H-azirin-3-amine 10a; its structure was also established by an X-ray crystal-structure determination (Fig. 3).
Esters of L-carnitine and acyl L-carnitine with hydoxy acids for
申请人：Avantgarde S.p.A.
公开号：US05627212A1
公开（公告）日：1997-05-06
Dermatosis is treated by a method comprising topically applying an effective amount of an ester of L-carnitine or an acyl L-carnitine with a hydroxy carboxylic acid selected from the group consisting of .alpha.-hydroxybutyric acid, .alpha.-hydroxyisocaproic acid, .alpha.-hydroxyisovaleric acid, malic acid and tartronic acid, to a patient in need thereof.
The present invention comprises small molecular weight, non-peptidic inhibitors of formula I and II of Protein Tyrosine Phosphatase 1 (PTP1) which are useful for the treatment and/or prevention of Non-Insulin Dependent Diabetes Mellitus (NIDDM).
