Approximately 90% of the administered drug is metabolized, predominantly by conjugation with glucuronic acid at the N-oxide position in the pyrimidine ring, but also by conversion to more polar products. Known metabolites exert much less pharmacologic effect than minoxidil itself.
Preliminary evidence suggests that the activity of minoxidil sulfotransferase (the enzyme that converts the drug to its sulfate) is higher in the hair follicle than in epidermis or dermis. Minoxidil sulfate, which may be formed preferentially in the hair follicle following topical application of the drug, exhibits more potent vasodilatory activity than the parent drug.
About 90% of an oral dose of minoxidil is metabolized, primarily by conjugation with glucuronic acid and also by conversion to more polar metabolites. Minoxidil's metabolites are considerably less active than the parent drug.
来源:Hazardous Substances Data Bank (HSDB)
代谢
米诺地尔（2,4-二氨基-6-哌啶嘧啶3-氧化物）在 rat、狗和猴子中的生物转化进行了研究，并与人类中报告的结果进行了比较。尿中代谢物的色谱图显示，每个物种排泄了实质上相同的代谢物，但相对量却大不相同。猴子和人类表现出相似的代谢物图谱，而狗和 rat 在数量上彼此不同，也不同于猴子和人类。猴子和人类的主要排泄产物是米诺地尔的葡萄糖苷酸结合物。这两个物种还排泄了少量未改变的米诺地尔、2,4-二氨基-6-(4'-羟基哌啶基)嘧啶3-氧化物以及更多极性的代谢物。rat 的主要排泄产物是未改变的米诺地尔。几乎同样多的（合计）两种酸性代谢物，2,4-二氨基-6-(4'-羧基正丁氨基)嘧啶及其3-氧化物也被产生。rat 还排泄了较小量的米诺地尔的葡萄糖苷酸、2,4-二氨基-6-(4'-羟基哌啶基)嘧啶3-氧化物、其3'-羟基异构体以及2,4-二氨基-6-哌啶嘧啶。狗排泄的米诺地尔的主要代谢物是4'-羟基代谢物。狗还排泄了较小量的未改变的米诺地尔和极性代谢物，以及更少的米诺地尔的葡萄糖苷酸、3'-羟基代谢物和2,4-二氨基-6-哌啶嘧啶。获得了狗血浆中4'-羟基代谢物葡萄糖苷酸结合物的证据。狗血浆中的主要循环物质是4'-羟基代谢物，而在猴子血浆中是米诺地尔的葡萄糖苷酸。
The biotransformation of minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was studied in the rat, dog, and monkey and compared to reported results in the human. Chromatographic profiles of urinary metabolites show that each species excreted substantially the same metabolites but in quite different relative amounts. The monkey and the human exhibited similar metabolite profiles, whereas the dog and rat were quantitatively different from each other and from the monkey and human. The major excretory product for the monkey and human was a glucuronide conjugate of minoxidil. Substantially smaller amounts of unchanged minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, and more polar metabolites also were excreted by these two species. The major excretory product in the rat was unchanged minoxidil. Almost as much (combined) of the two acidic metabolites, 2,4-diamino-6-(4'-carboxy-n-butylamino)pyrimidine and its 3-oxide, also were produced. Smaller amounts of the glucuronide of minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, its 3'-hydroxy isomer, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the rat. The major metabolite of minoxidil excreted by the dog was the 4'-hydroxy metabolite. Smaller amounts of unchanged minoxidil and polar metabolites and much smaller amounts of the glucuronide of minoxidil, the 3'-hydroxy metabolite, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the dog. Evidence was obtained for a glucuronide conjugate of the 4'-hydroxy metabolite in this species. The major circulatory material in dog plasma was the 4'-hydroxy metabolite, whereas it was the glucuronide of minoxidil in monkey plasma.
Serum aminotransferase elevations during oral minoxidil therapy are uncommon, but have been reported even with topical administration. Despite many decades of use, oral minoxidil has not been implicated in convincing cases of clinically apparent acute liver injury. Severe rash, toxic epidermal necrolysis and Stevens Johnson syndrome have been reported after minoxidil therapy (generally arising within 2 to 6 weeks of starting), but published cases have not been marked by concurrent hepatic injury.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，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：根据人类发生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
Minoxidil is almost completely absorbed (95%) from the GI tract. Peak plasma levels are reached in 1 hr. Protein binding does not occur. Minoxidil is widely distributed in the tissues, with an apparent volume of distribution of about 2.8-3.3 l/kg. Placental passage and distribution into breast milk have not been established. The elimination half-life of minoxidil is2.77-4.2 hr. About 90% of an oral dose of minoxidil is metabolized in the liver. The drug and its metabolites are largely excreted in the urine. Renal clearance is 73.9 ml/min.
Percutaneous absorption of minoxidil appears to be minimal following topical application of minoxidil solution to intact scalp. However, systemic absorption of topically applied minoxidil is variable and depends on several factors, including the vehicle used in the formulation, the area of application, condition of the skin (eg; being increased with local abrasion or inflammation), and interindividual variation in the extent of percutaneous absorption. Percutaneous absorption of the drug does not appear to be altered by use of a hot-air hair dryer. Although limited in vitro evidence suggests comparable release of minoxidil from solutions with different proportions of propylene glycol, alcohol, and water, release of the drug from a cream base differs substantially from that from solution formulations, and water-in-oil creams appear to differ markedly from oil-in-water creams or ointments in terms of the rate and concentration dependency of drug permeation through human skin. Absorption of minoxidil from extemporaneously prepared solutions, ointments, creams, or other such topical formulations may not be comparable to that from the commercially available topical minoxidil solution.
Percutaneous absorption of minoxidil following topical application of 2% hydroalcoholic, propylene glycol-containing solutions of the drug generally has been reported to average 0.3-4.5% of the applied dose. In a preliminary study in healthy balding men, the systemic bioavailability of minoxidil 2 or 3% topical solution (20 or 30 mg doses, respectively) at steady state relative to that of a 2.5 mg oral tablet averaged 1.4 or 1.2%, respectively. Based on urinary excretion of radiolabeled drug administered to healthy men in another study, percutaneous absorption of minoxidil after application of 1 or 5% minoxidil solutions to the scalp generally averaged 1.6-3.9% of the applied dose, based on urinary recovery of radiolabeled drug. In studies in animals, 5-36% of topically applied doses was absorbed systemically. Serum concentrations achieved after topical application of minoxidil solutions are variable, and clinical studies of topical minoxidil therapy have found no correlation between serum minoxidil concentrations and hair growth. In controlled studies in individuals with androgenetic alopecia or alopecia areata, serum concentrations of minoxidil after topical application of 1, 2, 3, or 5% solution formulations (with or without nightly petrolatum occlusion) generally averaged 2 ng/ml or less. However, about 1% of individuals receiving a 2% topical solution achieved peak serum concentrations of 5 ng/ml or greater, and a few patients achieved concentrations approaching 30 ng/ml. In part, increased percutaneous absorption of the drug in some individuals may have resulted from alterations in the stratum corneum (eg; secondary to irritation and inflammation from shaving of the scalp). In addition, some individuals may have a propensity for enhanced percutaneous absorption of the drug. Data from healthy balding men indicate that peak serum concentrations of unchanged minoxidil after oral doses of 5 mg daily generally are 20-30 times higher than mean serum concentrations achieved after twice daily topical application of approximately 20 mg (1 ml) of minoxidil as a 2% solution.
The distribution of topically applied minoxidil has not been fully determined. Limited evidence suggests that intact stratum corneum serves as a barrier that inhibits substantial diffusion of topically applied minoxidil into systemic circulation, but additional study is needed. Skin biopsy specimens obtained after topical application of a radiolabeled minoxidil 1 or 5% solution to the scalp of healthy balding men indicate an average retention in the skin of 2.6% or less of the applied dose after 24 hr, with twice as much radioactivity in the dermis as in the epidermis. The remainder of the dose remained on the skin or presumably was lost to the environment.
Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
申请人：Palani Anandan
公开号：US20060264489A1
公开（公告）日：2006-11-23
A compound having the general structure of Formula (I):
or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein:
Q is selected from the group consisting of:
and
L is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, are useful in treating diseases, disorders, or conditions such as metabolic syndrome and dyslipidemia.
The present invention relates to extracts of
Isochrysis
sp., preferably Tahitian
Isochrysis,
its cosmetic, dermatological and/or therapeutic uses and compositions and cosmetic, dermatological or therapeutic products comprising such an extract of
Isochrysis
sp., preferably Tahitian
Isochrysis.
FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
申请人：Corkey Britton Kenneth
公开号：US20120289493A1
公开（公告）日：2012-11-15
The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I:
wherein Q, R
1
, X
1
, X
2
, Y and R
2
are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.
[EN] INHIBITORS OF NHE-MEDIATED ANTIPORT<br/>[FR] INHIBITEURS D'ANTIPORT À MÉDIATION PAR NHE
申请人：ARDELYX INC
公开号：WO2018129557A1
公开（公告）日：2018-07-12
The present disclosure is directed to compounds (Ι') and to their use in methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds (Ι') and their use in methods for the treatment of hypertension. The present disclosure is also directed to compounds (Ι') and to their use in methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.
Hydroxylated nebivolol metabolites increase NO release from human endothelial cell preparations in a concentration dependent fashion following acute administration. In addition, hydroxylated nebivolol metabolites, including but not limited to 4-hydroxy-6,6′difluoro-, 4-hydroxy-5-phenol-6,6′difluoro-, and 4-hydroxy-8-pheno-6,6′difluoro-, have the ability to increase the capacity for NO release in human endothelial cells following chronic administration. This invention provides hydroxylated nebivolol metabolites and compositions comprising nebivolol and/or at least one hydroxylated metabolite of nebivolol and/or at least one additional compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof. In addition, this invention provides methods of treating and/or preventing vascular diseases by administering at least one hydroxylated metabolite of nebivolol that is capable of releasing a therapeutically effective amount of nitric oxide to a targeted site affected by the vascular disease. Also, this invention is directed to the treatment and/or prevention of migraine headaches administering at least one hydroxylated metabolite of nebivolol. This invention may also be used in conjunction with or as a single treatment of metabolic syndrome disorders.
