PDE5 (IC50 = 1.8 nM)

利用 IC (50)、K (D)（等温线）、K (D)（解离速率）和 K (D) ((1/2) EC (50)) 测定来确定生化效力（亲和力）这些化合物的 PDE5。结果显示以下化合物符合标准：西地那非（3.7 +/-1.4、4.8 +/-0.80、3.7 +/-0.29 和 11.7 +/-0.70 nM）、他达拉非（1.8 +/-0.40、2.4 +/ -0.60、1.9 +/-0.37 和 2.7 +/-0.25 nM)；和伐地那非（0.091 +/-0.031、0.38 +/-0.07、0.27 +/-0.01 和 0.42 +/-0.10 nM）。因此，每种抑制剂都具有相当的绝对效力值，其中伐地那非具有最高的相对效力，其次是他达拉非和西地那非[1]。将精液样本与 0.5 ml 不同浓度（分别为 0.2、0.1、0.05 和 0.025 μg ml-1）的他达拉非溶液混合。孵育两个小时后，用 0.2 μg ml-1 他达拉非处理的样品显示两组精子活力均显着增加 [2]。

他达拉非治疗组在 0.3、0.5、1、3 和 5 Hz 频率下的勃起功能（海绵体内压/平均动脉压）高于糖尿病组在接近对照值的可比频率下的值 [3]。口服 20 毫克他达拉非或 100 毫克西地那非。两组中计算机辅助精液分析的参数均不存在统计学上的显着变化。服用西地那非一小时和他达拉非两小时后，顶体早产反应的频率没有明显变化[2]。

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糖尿病大鼠表现为海绵状间隙扩张，平滑肌核异色，线粒体退化，细胞质空泡化，平滑肌免疫反应性阴性。神经纤维显示出厚厚的髓鞘和轴突内水肿，其中毛细血管显示出厚的基底膜。经Td治疗的糖尿病大鼠表现出海绵状组织的改善，平滑肌和弹性组织的面积百分比显著增加，纤维组织显著减少。Td治疗组在0.3、0.5、1、3和5 Hz的频率下显示出增强的勃起功能（海绵体内压/平均动脉压），与接近对照值的糖尿病组在相应频率下的值相比（P<0.05）。 结论：糖尿病大鼠长期低剂量给予Td可显著改善阴茎海绵体组织结构，增加平滑肌和弹性组织，减少纤维组织，增强勃起功能。这提出了这样一种观点，即经Td治疗后，阴茎结构的改变改善了勃起功能，超过了其半衰期，并改善了其对磷酸二酯酶5型的直接药理作用。[3]

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体内部分口服他达拉非（20mg）或西地那非（100mg）。在两组中，计算机辅助精液分析参数没有显著差异。服用他达拉非（2小时）和西地那非（1小时）后，未观察到顶体过早反应发生率的显著差异。考虑到体外和体内结果，急性按需服用他达拉非不会对精液参数产生不良影响[2]。

西地那非、他达拉非和伐地那非各自竞争性地抑制磷酸二酯酶-5（PDE5）对cGMP的水解，从而促进血管平滑肌的cGMP积累和舒张。这些化合物对PDE5的生化效力（亲和力）分别通过IC（50）、K（D）（等温线）、K的解离率和K的（1/2）EC（50）测定如下：西地那非（3.7+/-1.4、4.8+/-0.80、3.7+/-0.29和11.7+/-0.70 nM）、他达拉非（1.8+/-0.40、2.4+/-0.60、1.9+/-0.37和2.7+/-0.25 nM）；和伐地那非（0.091+/-0.031、0.38+/-0.07、0.27+/-0.01和0.42+/-0.10 nM）。因此，每种抑制剂的绝对效力值相似，相对效力为伐地那非>>他达拉非>西地那非。根据未标记化合物的作用，每种（3）H抑制剂与PDE5的结合都是特异性的。（3） H抑制剂不与分离的PDE5调节结构域结合。使用所有三（3）种H抑制剂相互竞争的EC（50）值的密切相关性表明，每种抑制剂在PDE5上占据相同的位点。对西地那非和伐地那非类似物的研究表明，伐地那非的效力更高是由于其双环的差异造成的。交换解离研究表明，每种抑制剂都有两种结合成分。过量的未标记抑制剂在无限稀释后对H抑制剂的解离没有显著影响，表明不存在亚基-亚基协同作用。cGMP的添加增加了[（3）H]他达拉非或[（3”H]伐地那非的结合亲和力，这一作用可能是由cGMP与PDE5变构位点的结合介导的，这意味着这两种抑制剂都通过提高cGMP来增强其自身与完整细胞中PDE5的结合。如果没有抑制剂，cGMP的积累会刺激cGMP的降解，但如果有抑制剂，这种负反馈过程会被阻断[1]。

体外[2]
分别从我们的男科门诊随机选取10名正常精子症患者和10名弱精子症患者。根据世界卫生组织（1999年）的指导方针，对正常精子精子精子样本进行了定义：精子计数>20×106 ml 1−1，精子活力>70%，精子形态异常<70%，活力>75%，白细胞<106 ml 1−1。入选患者（年龄26至40岁）接受了详细的病史和体检。排除接受PDE5抑制剂治疗的慢性前列腺炎、白细胞增多症或精索静脉曲张患者。
每位参与者都被要求在4-6天内保持禁欲，并在出席前12小时避免使用含咖啡因、酒精或尼古丁的药物。射精是在早上8点到10点之间通过手淫到一个干燥的广口无菌塑料容器中获得的。液化后，立即根据世界卫生组织的建议进行常规精液分析，以获得初步结果。
然后将样品在3毫升猎鹰管中分成六等份（每份0.5毫升）。一个作为空白对照，另一个加入1 mg ml-1己酮可可碱作为阳性对照（Nassar等人，1999）。对于其他试管，加入0.5 ml不同浓度的他达拉非溶液（分别为0.2、0.1、0.05和0.025μg ml−1）。他达拉非溶液是通过将其粉末溶解在生理盐水中制备的，最大浓度（0.2μg ml-1）是通过摄入20 mg他达拉非（最大推荐剂量）2小时后的最大精液含量确定的。己酮可可碱溶液是通过将其肠外溶液（100 mg 5 ml−1）加入95 ml−l生理盐水中制备的，使其最终浓度达到1 mg ml−1。

The study investigaged 48 adult male albino rats, comprising a control group, sham controls, streptozotocin-induced diabetic rats, and induced diabetic rats that received Td low-dose daily (0.09 mg/200 g weight) for 2 months. The rats were euthanized 1 day after the last dose. Cavernous tissues were subjected to histologic, immunohistochemical, morphometric studies, and measurement of intracavernosal pressure and mean arterial pressure in anesthetized rats.[3]

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Ten normozoospermic patients and ten asthenozoospermic patients were randomly picked up from our andrological outpatient department respectively. Inclusion and exclusion criteria were the same with in vitro part. Patients were randomly assigned to receive either drug: sildenafil (100 mg) or tadalafil (20 mg). They were then asked to collect semen samples 1 h or 2 h after sildenafil or tadalafil administration respectively. After a washout period for 7 days, each patient was crossed over to receive the other drug. Ejaculates obtain and requirements were the same with in vitro part. Specifically, sperm acrosome status was assessed by fluorescein isothiocyanate labelled peanut agglutinin (FITC-PNA) and propidium iodide (PI) (Sigma, Dorset, UK) staining and flow cytometry.[2]

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Dissovled in saline; 2 mg/kg; oral gavage

Sham-operated rats

Absorption, Distribution and Excretion
Tadalafil has a tmax of 0.5-6h with a median of 2h in healthy adults. The tmax in adults with PAH is reported as 2-8h with a median of 4h. There does not appear to be a significant effect on absorption when tadalafil is taken with food.
Tadalafil is primarily eliminated via hepatic metabolism. These metabolites are mainly excreted in the feces (61%) and to a lesser extent in the urine (36%)
Tadalafil has a mean apparent volume of distribution of 63L in healthy adults. The mean apparent volume of distribution is reported as 77L in adults with PAH.
The mean apparent oral clearance of tadalafil is 2.5-3.4L/h in healthy adults. The mean apparent oral clearance in adults with PAH is reported as 3.5L/h
Tmax: 30 minutes to 6 hours (median 2 hours). Absolute bioavailability has not been determined; rate and extent of absorption are not influenced by food.
Volume of distribution: 63 L; indicating distribution into tissues. Less than 0.0005% of administered dose was found in the semen of healthy subjects. 94% protein bound.
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once-daily dosing, and exposure is approximately 1.6-fold greater than after a single dose.
Elimination: Mean oral clearance: 2.5 L per hour. Fecal: 61%. Urine: 36%.
For more Absorption, Distribution and Excretion (Complete) data for TADALAFIL (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Tadalafil undergoes hepatic metabolism via CYP3A4 to a catechol metabolite. This catechol metabolite undergoes subsequent methylation and glucuronidation with the methyl-glucuronide metabolite becoming the primary metabolite in circulation. None of the known metabolites are considered to be active.
Biotransformation: Hepatic metabolism, mainly by CYP3A4. Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

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Biological Half-Life
The mean half-life of elimination of tadalafil is 15-17.5h in healthy adults. The mean half-life of elimination in adults with PAH is reported as 35h.
Terminal: 17.5 hours

Hepatotoxicity
Despite fairly extensive use, tadalafil has been linked to only rare reports of serum aminotransferase elevations and clinically apparent liver injury. In a single case report, tadalafil was linked to cholestatic hepatitis arising within a few days of starting the medication. Immunoallergic features and autoantibodies were not present. The injury was self-limiting without residual evidence of bile duct injury. The related PDE5 inhibitor, sildenafil, has also been associated with rare cases of acute cholestatic liver injury with jaundice.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of tadalafil during breastfeeding. An alternate agent may be preferred.
◉ 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.

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Protein Binding
Tadalafil is 94% bound to plasma proteins.

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Interactions
Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering the exposure (AUC) to tadalafil.
A significant interaction between tadalafil and nitroglycerin was observed to last up to 48 hours; at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered.
Administration of tadalafil to patients who are using any form of organic nitrates, either regularly and/or intermittently, is contraindicated; in clinical pharmacology studies tadalafil was shown to potentiate the hypotensive effects of nitrates; this is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway.
The safety and efficacy of combinations of tadalafil and other erectile dysfunctions have not been studied; use of combinations is not recommended.
For more Interactions (Complete) data for TADALAFIL (15 total), please visit the HSDB record page.

[1]. Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency,specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol. 2004 Jul;66(1):144-52.

[2]. Effect of acute tadalafil on sperm motility and acrosome reaction: in vitro and in vivo studies. Andrologia. 2013 Apr 14. [Epub ahead of print].

[3]. Effect of Chronic Low-dose Tadalafil on Penile Cavernous Tissues in Diabetic Rats. Urology. 2013 Jun;81(6):1253-60.

Therapeutic Uses
Tadalafil is indicated for the treatment of erectile dysfunction. /Included in US product labeling/

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Drug Warnings
The Food and Drug Administration ... approved updated labeling for Cialis, Levitra and Viagra to reflect a small number of post-marketing reports of sudden vision loss, attributed to NAION (non arteritic ischemic optic neuropathy), a condition where blood flow is blocked to the optic nerve. FDA advises patients to stop taking these medicines, and call a doctor or healthcare provider right away if they experience sudden or decreased vision loss in one or both eyes. Further, patients taking or considering taking these products should inform their health care professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of developing NAION again.
Cardiovascular status of patients should be considered since there is a degree of risk associated with sexual activity; treatments for erectile dysfunction, including tadalafil, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiac status.
The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for Cialis, and, therefore, the use of Cialis is not recommended in these groups until further information is available: patients with a myocardial infarction within the last 90 days, patients with unstable angina or angina occurring during sexual intercourse, patients with New York Heart Association Class 2 or greater heart failure in the last 6 months, patients with uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension (>170/100 mm Hg), and patients with a stroke within the last 6 months. In addition, patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.
The effect of a 100 mg single dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100 mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with /this/ dose of tadalafil compared to placebo was 3.1 beats per minute.
For more Drug Warnings (Complete) data for TADALAFIL (18 total), please visit the HSDB record page.

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Pharmacodynamics
Tadalafil exerts a therapeutic effect in ED by increasing sexual stimulation-dependant smooth muscle relaxation in the penis, allowing the corpus cavernosum to fill with blood to produce an erection. Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries. In BPH, tadalafil may contribute to decreased smooth muscle cell proliferation which may reduce the size of the prostate and relieve the anatomical obstruction which produces urinary symptoms of BPH. The decreased affinity of tadalafil for PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side effects.

C22H19N3O4

389.4

389.137

C, 67.86; H, 4.92; N, 10.79; O, 16.43

171596-29-5

Nortadalafil;171596-36-4;cis-Tadalafil;171596-27-3;ent-Tadalafil;629652-72-8;cis-ent-Tadalafil;171596-28-4;Tadalafil-d3;960226-55-5

110635

White to off-white solid powder

1.5±0.1 g/cm3

679.1±55.0 °C at 760 mmHg

298-300ºC

364.5±31.5 °C

0.0±2.1 mmHg at 25°C

1.758

1.43

74.87

1

4

1

29

702

2

CN1CC(=O)N2[C@@H](C1=O)CC3=C([C@H]2C4=CC5=C(C=C4)OCO5)NC6=CC=CC=C36

WOXKDUGGOYFFRN-IIBYNOLFSA-N

InChI=1S/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1

(6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

C-351; IC 351; Tadalafil; Cialis; 171596-29-5; Ic351; Tadanafil; ADCIRCA; ICOS 351; IC351; Trade names: Adcirca, Cialis

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.42 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 2 中的溶解度: 30% propylene glycol, 5% Tween 80, 65% D5W:30 mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。