PDE5 (IC50 = 0.7 nM); PDE6 (IC50 = 11 nM); PDE1 (IC50 = 180 nM); PDE3 (IC50 >1000 nM); PDE4 (IC50 >1000 nM)

Vardenafil Hydrochloride triHydrate 抑制 PDE5 介导的 cGMP 水解，IC50 为 0.7 nM[1]。盐酸伐地那非三水合物可提高阴茎海绵体组织中的细胞内 cGMP 水平，导致窦扩张和血流量增加 [3]。

在遭受海绵体神经损伤的大鼠中，盐酸伐地那非三水合物（IV；0.03 mg/kg）显示出促进作用[4]。盐酸伐地那非三水合物（IV；0.17 mg/kg，每日一次；7 天）可降低肝组织中 iNOS 和 NF-κB 的表达，并保护肝脏免受 Con A 诱导的肝炎[5]。在 ZDF 心脏中，盐酸伐地那非三水合物（PO；10 mg/kg，每日一次；25 周）可抑制 3-NT 产生的上升和组织 cGMP 水平的下降 [6]。

在这项研究中，研究人员调查了伐地那非对磷酸二酯酶（PDE）酶的效力和选择性，其改变cGMP代谢和引起阴茎平滑肌放松的能力，以及在外源性一氧化氮（NO）刺激条件下对体内勃起的影响。PDE同工酶从人血小板（PDE5）或牛来源（PDE 1、2、3、4和6）中提取和纯化。测定了伐地那非对这些PDE和人重组PDE的抑制作用。在体外测量了增强NO介导的松弛和影响人海绵体条中cGMP水平的能力，并在口服和静脉注射硝普钠（SNP）后，在清醒的兔子身上证明了勃起诱导活性。将伐地那非的效果与公认的PDE5抑制剂西地那非的效果进行了比较（括号内为西地那菲的值）。伐地那非特异性抑制PDE5对cGMP的水解，IC50为0.7 nM（6.6 nM）。相比之下，伐地那非对PDE1的IC50为180 nM；对PDE6的IC50为11 nM；对于PDE2、PDE3和PDE4的IC50超过1000 nM。相对于PDE5，PDE1的IC50比率为257（60），PDE6为16（7.4）。在3 nM（10 nM）的浓度下，伐地那非显著增强了SNP诱导的人小梁平滑肌松弛。伐地那非还显著增强了ACh诱导和透壁电刺激诱导的小梁平滑肌松弛。显著增强SNP诱导的cGMP积累的伐地那非最低浓度为3 nM（30 nM）[1]。

Animal/Disease Models: Male rat (9weeks old) underwent surgery for laparotomy or bilateral cavernous nerve (CN) crush injury[4]
Doses: 0.03 mg/kg
Route of Administration: intravenous (iv) injection
Experimental Results: Restored normal erectile responses with a combined administration of BAY 60-4552 (0.03, 0.3 mg/kg).

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Animal/Disease Models: Liver injury induced by Con A in male Swiss albino mice (20 ± 2 g)[5]
Doses: 0.17 mg/kg
Route of Administration: intravenous (iv) injection; one time/day, for 7 days; as a pretreatment
Experimental Results: decreased the levels of serum transaminases and alleviated Con A-induced hepatitis.

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Animal/Disease Models: Male 7weeks old Zucker diabetic fatty (ZDF) rats (preserved ejection fraction, HFpEF)[6]
Doses: 10 mg/kg
Route of Administration: po (oral gavage); one time/day, for 25 weeks
Experimental Results: Improved myofilament function in diabetic rat hearts.

Absorption
Over the recommended dose range, vardenafil has a dose-proportional pharmacokinetics profile. In healthy male volunteers given a single oral dose of 20 mg of vardenafil, maximum plasma concentrations were reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state, and 0.00018% of the dose was detected in semen 1.5 hours after dosing. Vardenafil has a bioavailability of approximately 15%. High-fat meals cause a Cmax reduction of 18%-50%; however, no changes were detected in AUC or Tmax.

Route of Elimination
Vardenafil is excreted as metabolites mainly through feces and urine. Approximately 91-95% of administered oral dose is found in feces, while 2-6% of administered oral dose is found in urine.

Volume of Distribution
Vardenafil has a steady-state volume of distribution of 208 L.

Clearance
Vardenafil has a total body clearance of 56 L/h.

Protein binding: Very high: 95% bound to plasma proteins; reversible and independent of total drug concentrations

Rapidly absorbed; absolute bioavailability is approximately 15%. Maximum observed plasma concentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state. A high-fat meal causes a reduction in Cmax by 18% to 50%.

Enhancement of nitric oxide (NO)-induced erections in rabbits by 0.1 mg/kg vardenafil is limited by its pharmacokinetic properties (Tmax=1 h; T1/2=1.2 h), although erectile effects have been observed after 7 h. In humans, vardenafil is rapidly absorbed (Tmax approximately 40 min) and more slowly metabolized (T1/2 approximately 4 h), with an absolute bioavailability of 14.5% (vs 40% for sildenafil). Although the consumption of high-fat meals does not affect the drug's relative bioavailability, it retards intestinal absorption. Coadministration of CYP3A4 inhibitors such as ritonavir can affect hepatic metabolism. M1, an active metabolite of vardenafil, is a four-fold-less potent inhibitor of PDE5 than its parent compound, contributing approximately 7% to vardenafil's overall efficacy. PMID:15224134

Time to peak concentration: 30 minutes to 2 hours (oral dosing, fasted state)

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Metabolism / Metabolites
Vardenafil is mainly metabolized by CYP3A4 in the liver, although CYP3A5 and CYP2C isoforms also contribute to its metabolism. The major circulating metabolite, M1 (N-desethylvardenafil), results from desethylation at the piperazine moiety of vardenafil, and has a plasma concentration of approximately 26% of that of the parent compound. M1 has a phosphodiesterase selectivity profile similar to that of vardenafil and an _in vitro_ inhibitory potency for PDE5 28% of that of vardenafil.

Hepatic metabolism, via CYP3A4, with contribution from CYP3A5 and CYP2C isoforms. Major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% of the parent compound and accounts for 7% of total pharmacologic activity. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil.

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Biological Half-Life
Vardenafil and its primary metabolite (M1) have a terminal half-life of 4-5 hours.

Hepatotoxicity
Despite fairly extensive use, vardenafil has not been associated with clinically apparent cases of liver injury and serum enzyme elevations during therapy are rare. The related PDE5 inhibitors, sildenafil and tadalafil have been linked to isolated, rare instances of acute liver injury and jaundice. The latency to onset ranged from a few days to 3 months and the pattern of injury was usually cholestatic. Autoimmune and immunoallergic features were not observed and all cases were self-limited without residual injury or acute liver failure. Whether vardenafil can cause a similar form of acute liver injury is unknown.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Interactions
Vardenafil has not been studied in combination with other treatments for erectile dysfunction; use of combination erectile dysfunction medication is not recommended.

Alpha-blockers, such as: Terazosin, tamsulosin, doxazosin, prazosin, alfuzosin: Use is contraindicated; co-administration can produce hypotension)

Erythromycin produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax /when administered to healthy volunteers/.

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Protein Binding
Approximately 95% of vardenafil and its major circulating metabolite is bound to plasma proteins. Their protein binding is reversible and independent of total drug concentrations.

[1]. The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res. 2001;13(5):282-290.

[2]. Vardenafil dihydrochloride. Profiles Drug Subst Excip Relat Methodol. 2014;39:515-544.

[3]. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil--review of the literature. Eur J Med Res. 2002 Oct 29. 7(10):435-46.

[4]. Combination of BAY 60-4552 and vardenafil exerts proerectile facilitator effects in rats with cavernous nerve injury: a proof of concept study for the treatment of phosphodiesterase type 5 inhibitor failure. Eur Urol. 2011 Nov. 60(5):1020-6.

[5]. Hepatoprotective role of vardenafil against experimentally induced hepatitis in mice. J Biochem Mol Toxicol. 2017 Mar. 31(3).

[6]. Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts. Antioxidants (Basel). 2021 Nov 6. 10(11):1776.

Vardenafil Hydrochloride Trihydrate is the hydrochloride salt form of vardenafil, a benzenesulfonamide derivative and phosphodiesterase type 5 (PDE5) inhibitor with vasodilatory activity. Vardenafil selectively inhibits PDE5, thus inhibiting the degradation of cyclic guanosine monophosphate (cGMP) found in the smooth muscle of the corpus cavernosa and corpus spongiosum of the penis. The inhibition of cGMP degradation results in prolonged muscle relaxation, vasodilation, and blood engorgement of the corpus cavernosa, thereby prolonging penile erection.
A piperazine derivative, PHOSPHODIESTERASE 5 INHIBITOR and VASODILATOR AGENT that is used as a UROLOGICAL AGENT in the treatment of ERECTILE DYSFUNCTION.
See also: Vardenafil (annotation moved to).

C23H32N6O4S.HCL.3H2O

579.11

578.229

C, 44.88; H, 6.55; Cl, 11.52; N, 13.65; O, 18.19; S, 5.21

330808-88-3

Vardenafil hydrochloride;224785-91-5;Vardenafil dihydrochloride;224789-15-5

135413545

White to light yellow solid powder

3.636

148.97

5

11

8

38

854

0

O=C1N=C(C2=CC(S(=O)(N3CCN(CC)CC3)=O)=CC=C2OCC)NN4C1=C(C)N=C4CCC.[H]Cl.[H]O[H].[H]O[H].[H]O[H]

NEAUGLIJDBPHAY-UHFFFAOYSA-N

InChI=1S/C23H32N6O4S.ClH.3H2O/c1-5-8-20-24-16(4)21-23(30)25-22(26-29(20)21)18-15-17(9-10-19(18)33-7-3)34(31,32)28-13-11-27(6-2)12-14-28;;;;/h9-10,15H,5-8,11-14H2,1-4H3,(H,25,26,30);1H;3*1H2

2-(2-ethoxy-5-((4-ethylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(1H)-one dihydrochloride trihydrate

BAY38-9456; BAY 38-9456; 224785-91-5; Vardenafil HCL; Vardenafil (hydrochloride); Vardenafilhydrochloride; Vardenafil, Hydrochloride Salt; Vardenafil hydrochloride [USAN]; VARDENAFIL MONOHYDROCHLORIDE;BAY-38-9456; trade names: Levitra; Staxyn; Vivanza; Vardenafil hydrochloride trihydrate; Vardenafil HCl; Levitra; Staxyn; Vivanza

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。