calcium;(E,3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoic acid | 147511-69-1

• 物质功能分类: 原料药 - 循环系统用药 - 调节血脂药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: calcium;(E,3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoic acid
• CAS: 147511-69-1
• 化学式: C25H24CaFNO4+2
• 分子量: 461.5
• InChiKey: VSQHXQMFUCHGBD-NRFPMOEYSA-N

物化性质

• 熔点：
  182 - 185°C
• 沸点：
  692.0±55.0 °C(Predicted)
• 密度：
  1.352±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 蒸汽压力：
  2.32X10-17 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 4.3 (carboxy) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.14
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  90.6
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

匹伐他汀对大鼠肝脏微粒体药物代谢的影响已经进行了研究，并且测量了多种药物代谢酶的活性。与对照相比，在连续7天以1-10 mg/kg/天的剂量给予匹伐他汀后，未发现药物代谢酶（苯胺羟基酶、氨基比林N-脱甲基酶、7-乙氧基香豆素O-脱乙基酶和UDP-葡萄糖醛酸转移酶）的诱导。基于多种不同的体外方法，可以得出结论，CYP2C9是负责匹伐他汀代谢的酶，并且在肾脏和肠道微粒体中没有发现代谢物。CYP2C9的多态性与匹伐他汀的代谢无关。在匹伐他汀存在下，未检测到对托烷咪唑4-羟基化（CYP2C9）和睾酮6β-羟基化（CYP3A4）的CYP介导代谢的抑制效应。结果表明，匹伐他汀不会影响药物代谢系统。

Pitavastatin has been studied for its effects on hepatic microsomal drug metabolism in rats, and the activities of several drug-metabolizing enzymes have been measured. No induction of the drug metabolizing enzymes (aniline hydroxylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase and UDP-glucuronic acid transferase) was found in the pitavastatin group compared to the control after the multiple administrations of pitavastatin at the dosage of 1-10 mg/kg per day for 7 days. Based on several different in vitro approaches, it is concluded that CYP2C9 is the enzyme responsible for the metabolism of pitavastatin and no metabolite is present in renal and intestinal microsomes. The CYP2C9 polymorphism was not involved in the pitavastatin metabolism. No inhibitory effect in CYP-mediated metabolism was detected on the tolbutamide 4-hydroxylation (CYP2C9) and testosterone 6 beta-hydroxylation (CYP3A4) in the presence of pitavastatin. The results suggested that pitavastatin did not affect the drug-metabolizing systems.

来源:Hazardous Substances Data Bank (HSDB)

代谢

匹伐他汀通过CYP2C9进行轻微代谢，在较小程度上通过CYP2C8。人类血浆中的主要代谢物是乳酮，它是通过尿苷5'-二磷酸（UDP）葡萄糖醛酸基转移酶（UGT1A3和UGT2B7）形成的酯型匹伐他汀葡萄糖醛酸苷共轭物。

Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).

来源:Hazardous Substances Data Bank (HSDB)

代谢

为了阐明可能的物种差异，研究了大鼠、狗、兔、猴子和人类肝脏和肾脏微粒体中匹伐他汀及其内酯的体外代谢。在向肝脏微粒体中添加UDP-葡萄糖醛酸时，匹伐他汀内酯被确定为包括人类在内的几种动物中的主要代谢物。匹伐他汀及其内酯在猴肝微粒体中的代谢清除率远大于人类。匹伐他汀的3-脱羟基结构代谢物M4在猴肝微粒体中UDP-葡萄糖醛酸的存在下转化为其内酯形式，以及转化为匹伐他汀。这些结果表明，内酯化是5-羟基戊酸衍生物等药物的常见代谢途径。由于结构特性，酸形式被代谢为它们的内酯形式。UDP-葡萄糖醛酸基转移酶是负责匹伐他汀内酯化的关键酶，总体代谢与人类不同，因为猴子对匹伐他汀及其内酯进行了广泛的氧化代谢。

To elucidate any potential species differences, the in vitro metabolism of pitavastatin and its lactone was studied with hepatic and renal microsomes from rats, dogs, rabbits, monkeys and humans. With the addition of UDP-glucuronic acid to hepatic microsomes, pitavastatin lactone was identified as the main metabolite in several animals, including humans. Metabolic clearances of pitavastatin and its lactone in monkey hepatic microsome were much greater than in humans. M4, a metabolite of pitavastatin with a 3-dehydroxy structure, was converted to its lactone form in monkey hepatic microsomes in the presence of UDP-glucuronic acid as well as to pitavastatin. These results implied that lactonization is a common pathway for drugs such as 5-hydroxy pentanoic acid derivatives. The acid forms were metabolized to their lactone forms because of their structural characteristics. UDP-glucuronosyltransferase is the key enzyme responsible for the lactonization of pitavastatin, and overall metabolism is different compared with humans owing to the extensive oxidative metabolism of pitavastatin and its lactone in monkey.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：匹伐他汀是一种羟甲戊二酸辅酶A（HMG-CoA）还原酶抑制剂（即他汀类药物），是一种降脂药。它被用作生活方式改变的辅助手段，用于管理血脂异常。人类暴露和毒性：匹伐他汀禁用于孕妇或患有活动性肝病的患者，包括血清转氨酶浓度持续不明原因升高的情况。已经报道了使用HMG-CoA还原酶抑制剂，包括匹伐他汀，导致的肌病和横纹肌溶解症，并伴有急性肾功能衰竭和肌红蛋白尿。这些风险可能在任何剂量水平下发生，但会以剂量依赖性方式增加。在接受匹伐他汀治疗的患者中，也有罕见报道出现致命和非致命的肝衰竭病例。动物研究：在一项为期92周的致癌性研究中，给予小鼠匹伐他汀，在最大耐受剂量75 mg/kg/天时，没有出现药物相关的肿瘤。然而，在一项为期92周的致癌性研究中，给予大鼠口服匹伐他汀1、5、25 mg/kg/天，25 mg/kg/天时甲状腺滤泡细胞肿瘤的发生率显著增加。在器官形成期，对怀孕大鼠进行胚胎-胎儿发育研究，给予3、10、30 mg/kg/天的匹伐他汀口服灌胃，3 mg/kg/天时没有观察到不良影响。在胎儿器官形成期，对怀孕兔子进行胚胎-胎儿发育研究，给予0.1、0.3、1 mg/kg/天的匹伐他汀口服灌胃，所有测试剂量下都观察到母体毒性，包括体重减轻和流产。在围产期/产后研究中，对怀孕大鼠从器官形成期到断奶期间给予口服灌胃剂量的匹伐他汀0.1、0.3、1、3、10、30 mg/kg/天，0.3 mg/kg/天时母体毒性导致死亡，所有剂量下泌乳受损，导致所有剂量组的新生儿存活率降低。匹伐他汀在10和30 mg/kg/天的口服剂量下对雄性和雌性大鼠的生育能力没有不良影响。匹伐他汀在沙门氏菌和李斯特菌的Ames试验中，无论是否经过代谢激活，在小鼠单次给药和在大鼠多次给药后的微核试验中，在大鼠的不定期DNA合成试验中，以及在小鼠的Comet试验中均不具有致突变性。在染色体畸变试验中，观察到最高测试剂量下的致裂变性，同时也引起了高水平的细胞毒性。

IDENTIFICATION AND USE: Pitavastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent. It is used as an adjunct to lifestyle modifications for the management of dyslipidemias. HUMAN EXPOSURE AND TOXICITY: Pitavastatin is contraindicated for use in pregnant women or patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations. Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including pitavastatin. These risks can occur at any dose level, but increase in a dose-dependent manner. Cases of fatal and nonfatal hepatic failure have also been reported rarely in patients receiving pitavastatin. ANIMAL STUDIES: In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day there was an absence of drug-related tumors. However, in a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage, there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day. Embryo-fetal developmental studies were conducted in pregnant rats treated with 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. No adverse effects were observed at 3 mg/kg/day. Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested. In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at 0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups. Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively. Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested which also elicited high levels of cytotoxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的使用总结：目前没有关于母乳喂养期间使用匹伐他汀的已发表信息。它有99%与血浆蛋白结合，因此乳汁中的量可能很低。由于担心干扰婴儿的脂质代谢，共识认为在母乳喂养期间不应使用匹伐他汀。然而，也有人认为，对于家族性高胆固醇血症的纯合子儿童从1岁开始就用他汀类药物治疗，他汀类药物的口服生物利用度低，对哺乳婴儿的风险很低，尤其是瑞舒伐他汀和普伐他汀。在更多数据可用之前，可以选择其他药物，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发表信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发表信息。

◉ Summary of Use during Lactation:No published information exists on the use of pitavastatin during breastfeeding. It is 99% bound to plasma proteins, so amounts in milk are likely low. Because of a concern with disruption of infant lipid metabolism, the consensus is that pitavastatin should not be used during breastfeeding. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with rosuvastatin and pravastatin. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

Pitavastatin 是有机阴离子转运多肽（OATP）1B1（OATP2）的底物。抑制 OATP1B1（例如，环孢素、红霉素、利福平）的药物可以提高 Pitavastatin 的生物利用度。

Pitavastatin is a substrate of organic anionic transport polypeptide (OATP) 1B1 (OATP2). Drugs that inhibit OATP1B1 (e.g., cyclosporine, erythromycin, rifampin) can increase bioavailability of pitavastatin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与pitavastatin（2毫克，每日一次）和ezetimibe（10毫克，连续7天）联合使用时，pitavastatin的峰血浆浓度和AUC分别下降了2%和0.2%，而ezetimibe的峰血浆浓度和AUC分别增加了9%和2%。

Concomitant use of pitavastatin (2 mg once daily) and ezetimibe (10 mg for 7 days) decreased pitavastatin peak plasma concentration and AUC by 2 and 0.2%, respectively, and increased ezetimibe peak plasma concentration and AUC by 9 and 2%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

红霉素显著增加匹伐他汀的暴露量。1在匹伐他汀（第4天单次剂量4毫克）和红霉素（每天4次，每次500毫克，连续6天）联合使用后，匹伐他汀的峰血浆浓度和AUC分别增加了3.6倍和2.8倍；这些效果被认为是临床重要的。匹伐他汀与红霉素之间的相互作用可能是由于红霉素抑制了有机阴离子转运多肽（OATP）1B1介导的匹伐他汀的肝脏摄取。如果与红霉素同时使用，匹伐他汀的剂量不应超过每天一次1毫克。

Erythromycin substantially increases pitavastatin exposure.1 Following concomitant use of pitavastatin (4 mg as a single dose on day 4) and erythromycin (500 mg 4 times daily for 6 days), pitavastatin peak plasma concentration and AUC were increased by 3.6- and 2.8-fold, respectively; such effects were considered clinically important. The interaction between pitavastatin and erythromycin probably resulted partly from erythromycin-induced inhibition of organic anionic transport polypeptide (OATP)1B1-mediated hepatic uptake of pitavastatin. If used concomitantly with erythromycin, dosage of pitavastatin should not exceed 1 mg once daily.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

/MILK/ 目前尚不清楚pitavastatin是否会在人类乳汁中排泄，但是已经显示，这类药物中的另一种药物会少量进入人类乳汁。大鼠研究表明，pitavastatin会排泄到母乳中。

/MILK/ It is not known whether pitavastatin is excreted in human milk, however, it has been shown that a small amount of another drug in this class passes into human milk. Rat studies have shown that pitavastatin is excreted into breast milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这项研究旨在了解SLCO1B1基因变异对两种OATP1B1底物——普伐他汀和匹伐他汀的处置及其转运活性的影响机制。SLCO1B1编码OATP1B1（有机阴离子转运多肽）转运蛋白。实验测量了在过表达SLCO1B1*1a和SLCO1B1*15的卵母细胞中对普伐他汀、匹伐他汀和氟伐他汀的摄取，以比较体外转运活性的变化。在11名健康志愿者中，给予40毫克普伐他汀或4毫克匹伐他汀，这些志愿者分别具有SLCO1B1*1a/*1a和SLCO1B1*15/*15的纯合基因型，然后比较了普伐他汀和匹伐他汀的药代动力学参数。与SLCO1B1*1a相比，SLCO1B1*15过表达的卵母细胞对普伐他汀和匹伐他汀的摄取降低，但对氟伐他汀没有变化。匹伐他汀在SLCO1B1*15与SLCO1B1*1a相比的体外内在清除率（Clint）倍数变化大于普伐他汀（P<0.0001）。匹伐他汀的清除率（Cl/F）在SLCO1B1*15/*15基因型的参与者中降低的程度比普伐他汀更大（P<0.01），与体外研究一致。因此，非代谢底物的Cmax和血浆浓度-时间曲线下面积由于SLCO1B1*15变异而增加。然而，SLCO1B1*15变异与SLCO1B1*1a相比，匹伐他汀的转运活性降低更多，这与SLCO1B1基因多态性对匹伐他汀的药代动力学影响大于普伐他汀有关。这项研究表明，SLCO1B1*15变异的底物依赖性可能会调节SLCO1B1多态性对普伐他汀和匹伐他汀处置的影响。

This study was addressed to understand the underlying mechanism of the substrate-dependent effect of genetic variation in SLCO1B1, which encodes OATP1B1 (organic anion transporting polypeptide) transporter, on the disposition of two OATP1B1 substrates, pravastatin and pitavastatin, in relation to their transport activities. The uptake of pravastatin, pitavastatin, and fluvastatin was measured in oocytes overexpressing SLCO1B1*1a and SLCO1B1*15 to compare the alterations of in-vitro transporting activity. After 40-mg pravastatin or 4-mg pitavastatin was administered to 11 healthy volunteers with homozygous genotypes of SLCO1B1*1a/*1a and SLCO1B1*15/*15, the pharmacokinetic parameters of pravastatin and pitavastatin were compared among participants with SLCO1B1*1a/*1a and SLCO1B1*15/*15 genotypes. The uptake of pravastatin and pitavastatin in SLCO1B1*15 overexpressing oocytes was decreased compared with that in SLCO1B1*15, but no change occurred with fluvastatin. The fold change of in-vitro intrinsic clearance (Clint) for pitavastatin in SLCO1B1*15 compared with SLCO1B1*1a was larger than that of pravastatin (P<0.0001). The clearance (Cl/F) of pitavastatin was decreased to a greater degree in participant with SLCO1B1*15/*15 compared with that of pravastatin in vivo (P<0.01), consistent with in-vitro study. As a result, Cmax and area under the plasma concentration-time curve of these nonmetabolized substrates were increased by SLCO1B1*15 variant. The greater decrease