Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Valsartan is known to be excreted largely as unchanged compound and is minimally metabolized in man. Although the only notable metabolite is 4-hydroxyvaleryl metabolite (4-OH valsartan), the responsible enzyme has not been clarified at present. The current in vitro studies were conducted to identify the cytochrome P450 (CYP) enzymes involved in the formation of 4-OH valsartan. Valsartan was metabolized to 4-OH valsartan by human liver microsomes and the Eadie-Hofstee plots were linear. The apparent Km and Vmax values for the formation of 4-OH valsartan were 41.9-55.8 microM and 27.2-216.9 pmol min(-1) mg(-1) protein, respectively. There was good correlation between the formation rates of 4-OH valsartan and diclofenac 4'-hydroxylase activities (representative CYP2C9 activity) of 11 individual microsomes (r = 0.889). No good correlation was observed between any of the other CYP enzyme marker activities (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A). Among the recombinant CYP enzymes examined (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5 and 4A11), CYP2C9 notably catalysed 4-hydroxylation of valsartan. For the specific CYP inhibitors or substrates examined (furafylline, diclofenac, S(+)-mephenytoin, quinidine and troleandomycin), only diclofenac inhibited the formation of 4-OH valsartan. These results showed that CYP2C9 is the only form responsible for 4-hydroxylation of valsartan in human liver microsomes. Although CYP2C9 is involved in valsartan metabolism, CYP-mediated drug-drug interaction between valsartan and other co-administered drugs would be negligible.
... Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. ...
来源:Hazardous Substances Data Bank (HSDB)
代谢
Valsartan 已知的人类代谢物包括 4-羟基-valsartan。
Valsartan has known human metabolites that include 4-hydroxy-valsartan.
IDENTIFICATION AND USE: Valsartan is a white to practically white fine powder that is formulated into oral tablets. Valsartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used in the management of hypertension. Valsartan is also used to treat heart failure or left ventricular dysfunction after acute myocardial infarction. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of overdosage include hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed levels of consciousness, circulatory collapse and shock have been reported. The use of valsartan during pregnancy is contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, prematurity, and patent ductus arteriosus. Anuria-associated anhydramnios/oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to valsartan. ANIMAL STUDIES: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to two years. Also, valsartan had no adverse effects on fertility of male or female rats and no teratogenic effects were observed when valsartan was administered to pregnant mice and rats. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses during organogenesis or late gestation and lactation. In rabbits, maternal toxic doses resulted in fetal resorptions, litter loss, abortions, and low fetal body weight as well as maternal mortality. Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
肝毒性
Valsartan 已与血清转氨酶升高的低发生率有关（
Valsartan has been associated with a low rate of serum aminotransferase elevations (
After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration.
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.
来源:DrugBank
吸收、分配和排泄
分布容积
静脉给药后，缬沙坦的稳态分布容积较小（17升），这表明缬沙坦不会广泛分布到组织中。
The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively.
Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance).
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. ... Following intravenous administration, plasma clearance of valsartan is about 2 L/hr and its renal clearance is 0.62 L/hr (about 30% of total clearance).
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic 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。
