Gemfibrozil undergoes hydroxylation at the 5'-methyl and 4' positions to form the M1 and M2 metaolites respectively. Gemfibrozil also undergoes O-glucuronidation to form gemfibrozil 1-beta glucuronide, an inhibitor of CYP2C8. This O-glucuronidation is primarily mediated by UGT2B7, but also by UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B17.
Gemfibrozil is biotransformed extensively following oral administration. A major pathway of gemfibrozil metabolism is via glucuronidation. Following a single oral administration of 450 mg (6 mg/kg bw est) gemfibrozil to six male subjects, gemfibrozil glucuronide represented approximately 50% of the total urinary metabolites (32% of the dose) recovered within 24 hr. Very similar results had been obtained in /another/ ... study, in which 31% of the dose was recovered as urinary gemfibrozil glucuronide over 0-48 hr. Among metabolites resulting from phase I biotransformation, 5-(5-carboxy-2-methylphenoxy)-2,2-dimethyl pentanoic acid (M3) was the major metabolite recovered. ... A 24-hr urine collection contained both free and conjugated M3 at approximately 15% and 5% of the total dose, respectively, while, in /another/ study, free and conjugated M3 represented approximately 7% and 5% of the recovered radiactivity, respectively. Other minor metabolites identified were the 5-hydroxymethyl derivative (M2, an intermediate in the pathway to M3), a 4-hydroxy derivative (M1) and a 2- hydroxymethyl derivative (M4). In aggregate, urinary and fecal excretion of radioactivity accounted for 66% and 6%, respectively, of the elimination of orally administered gemfibrozil over five days.
The exact metabolic fate of gemfibrozil has not been fully elucidated, but the drug appears to be metabolized in the liver to 4 major metabolites produced via 3 metabolic pathways. Gemfibrozil undergoes hydroxylation of the m-methyl group to the corresponding benzyl alcohol derivative (metabolite II), which is rapidly oxidized to a benzoic acid metabolite (metabolite III, 3-[(4-carboxy-4-methylpentyl)oxy]-4-methylbenzoic acid), the major metabolite. The drug also undergoes hydroxylation of the aromatic ring to produce a phenol derivative (metabolite I) which is probably further metabolized to a compound that is phenolic but has no intact carboxylic acid function (metabolite IV). Metabolite I is pharmacologically active. The drug and its metabolites also undergo conjugation.
The roles of multidrug resistance-associated protein (Mrp) 2 deficiency and Mrp3 up-regulation were evaluated on the metabolism and disposition of gemfibrozil. Results from in vitro studies in microsomes showed that the hepatic intrinsic clearance (CLint) for the oxidative metabolism of gemfibrozil was slightly higher (1.5-fold) in male TR- rats, which are deficient in Mrp2, than in wild-type Wistar rats, whereas CLint for glucuronidation was similar in both strains. The biliary excretion of intravenously administered [14C]gemfibrozil was significantly impaired in TR-) rats compared with Wistar rats (22 versus 93% of the dose excreted as the acyl glucuronides over 72 h). Additionally, the extent of urinary excretion of radioactivity was much higher in TR- than in Wistar rats (78 versus 2.6% of the dose). There were complex time-dependent changes in the total radioactivity levels and metabolite profiles in plasma, liver and kidney, some of which appeared to be related to the up-regulation of Mrp3. Overall, it was demonstrated that alterations in the expression of the transporters Mrp2 and Mrp3 significantly affected the excretion as well as the secondary metabolism and distribution of (14)Cgemfibrozil.
... (14)C-Gemfibrozil was administered orally to rats at a dose of 2000 mg/kg. At various time points, radioactivity in urine was analyzed by liquid scintillation spectrometry, high-pressure liquid chromatography, liquid chromatography/mass spectrometry, gas chromatography/mass spectroscopy, and nuclear magnetic resonance. Nine metabolites of gemfibrozil were identified, some that have not been reported previously. Although the majority of metabolites were glucuronidated, some nonglucuronidated metabolites were identified in urine, including a diol metabolite (both ring methyls hydroxylated), and the product of its further metabolism, the acid-alcohol derivative (ortho ring methyl hydroxylated, meta ring methyl completely oxidized to the acid). Hydroxylation of the aromatic ring also was a common pathway for gemfibrozil metabolism, leading to the production of two phenolic metabolites, only one of which was detected in the urine in the nonconjugated or free form. Also of interest was the finding that both acyl and ether glucuronides were produced, including both glucuronide forms of the same metabolite (e. g., 1-O-GlcUA, 5'-COOH-gemfibrozil, and 5'-COO-GlcUA-gemfibrozil); the positions and functionality of the glucuronide conjugates were identified using base hydrolysis or glucuronidase treatment, in combination with liquid chromatography/MS and nuclear magnetic resonance.
Gemfibrozil increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis. It does so by activating Peroxisome proliferator-activated receptor-alpha (PPAR‘±) 'transcription factor ligand', a receptor that is involved in metabolism of carbohydrates and fats, as well as adipose tissue differentiation. This increase in the synthesis of lipoprotein lipase thereby increases the clearance of triglycerides. Chylomicrons are degraded, VLDLs are converted to LDLs, and LDLs are converted to HDL. This is accompanied by a slight increase in secretion of lipids into the bile and ultimately the intestine. Gemfibrozil also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL.
Mild, transient serum aminotransferase elevations develop in approximately 20% of patients receiving gemfibrozil, but values above 3 times normal in 5% or less. These abnormalities are usually asymptomatic and transient, resolving even with continuation. However, there have also been rare reports of clinically apparent liver injury in patients on long term gemfibrozil. The clinical presentation was highly variable. The onset of injury varied from a few weeks to several years after starting the medication and the pattern of serum enzyme elevations ranged from hepatocellular (Case 1) to mixed to cholestatic. Cases have not been associated with signs of immunoallergic (fever, rash, eosinophilia) or autoimmune hepatitis and recovery has been prompt and complete with stopping therapy.
Gemfibrozil is absorbed from the gastrointestinal tract. In healthy volunteers, a 900mg oral dose of gemfibrozil has a Cmax of 46±16µg/mL with a Tmax of 2.2±1.1h. In patients with chronic renal failure, gemfibrozil has a Cmax of 13.8±11.1µg/mL with a Tmax of 2.3±1.0h. In patients with liver disease, gemfibrozil has a Cmax of 23.0±10.3µg/mL with a Tmax of 2.6±1.7h.
Approximately 70% of a dose of gemfibrozil is eliminated in the urine. The majority of a dose is eliminated as a glucuronide conjugate and <2% is elimiinated as the unmetabolized drug. 6% of a dose is eliminated in the feces. In healthy volunteers, 0.02-0.15% of a dose was detected in the urine as unmetabolized gemfibrozil, with 7-14% detected as conjugated metabolites. In patients with renal failure, trace amounts of unmetabolized gemfibrozil is present in the urine, with 0.5-9.8% detected as conjugated metabolites. In patients with liver disease, 0.1-0.2% of a dose was detected in the urine as unmetabolized gemfibrozil, with 25-50% detected as conjugated metabolites.
来源:DrugBank
吸收、分配和排泄
分布容积
吉非罗齐的分布体积估计为0.8L/kg。
The volume of distribution of gemfibrozil is estimated to be 0.8L/kg.
来源:DrugBank
吸收、分配和排泄
清除
吉非罗齐的清除率估计为6.0L/h。
The clearance of gemfibrozil is estimated to be 6.0L/h.
来源:DrugBank
吸收、分配和排泄
恒河猴研究表明吉非罗齐可以穿过胎盘。
Studies in monkeys indicate that gemfibrozil crosses the placenta.
Small molecules for treatment of hypercholesterolemia and related diseases
申请人：Sircar C. Jagadish
公开号：US20050277690A1
公开（公告）日：2005-12-15
The present invention provides compositions adapted to enhance reverse cholesterol transport in mammals. The compositions are suitable for oral delivery and useful in the treatment and/or prevention of hypercholesterolemia, atherosclerosis and associated cardiovascular diseases.
[EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
申请人：AMGEN INC
公开号：WO2013123444A1
公开（公告）日：2013-08-22
The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
申请人：Ryono Denis E.
公开号：US20080009465A1
公开（公告）日：2008-01-10
Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure
wherein
is a heteroaryl ring;
R
4
is —(CH
2
)
n
-Z-(CH
2
)
m
—PO(OR
7
)(OR
8
), —(CH
2
)
n
Z-(CH
2
)
m
—PO(OR
7
)R
g
, —(CH
2
)
n
-Z-(CH
2
)
m
—OPO(OR
7
)R
g
, —(CH
2
)
n
Z—(CH
2
)
m
—OPO(R
9
)(R
10
), or —(CH
2
)
n
Z—(CH
2
)
m
—PO(R
9
)(R
10
);
R
5
and R
6
are independently selected from H, alkyl and halogen;
Y is R
7
(CH
2
)
s
or is absent; and
X, n, Z, m, R
4
, R
5
, R
6
, R
7
, and s are as defined herein; or a pharmaceutically acceptable salt thereof.
A method for treating diabetes and related diseases employing the above compounds is also provided.
提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构：
其中
是杂环芳基环；
R
4
为—(CH
2
)
n
-Z-(CH
2
)
m
—PO(OR
7
)(OR
8
)、—(CH
2
)
n
Z-(CH
2
)
m
—PO(OR
7
)R
g
、—(CH
2
)
n
-Z-(CH
2
)
m
—OPO(OR
7
)R
g
、—(CH
2
)
n
Z—(CH
2
)
m
—OPO(R
9
)(R
10)
或—(CH
2
)
n
Z—(CH
2
)
m
—PO(R
9
)(R
10)
；
R
5
和R
6
分别选择自H、烷基和卤素；
Y为R
7
(CH
2
)
s
或不存在；以及
X、n、Z、m、R
4
、R
5
、R
6
、R
7
和s如本文所定义；或其药用盐。
还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
