PDE5 (IC50 = 1.8 nM)

The assays IC (50), K (D) (isotherm), K (D) (dissociation rate), and K (D) ((1/2) EC (50)) were utilized to ascertain the biochemical potency (affinity) of these compounds for PDE5. The results showed that the following compounds met the criteria: sildenafil (3.7 +/-1.4, 4.8 +/-0.80, 3.7 +/-0.29 and 11.7 +/-0.70 nM), Tadalafil (1.8 +/-0.40, 2.4 +/-0.60, 1.9 +/-0.37 and 2.7 +/-0.25 nM); and vardenafil (0.091 +/-0.031, 0.38 +/-0.07, 0.27 +/-0.01 and 0.42 +/-0.10 nM). As a result, each inhibitor has comparable absolute potency values, with vardenafil having the highest relative potency followed by tadalafil and sildenafil [1]. The semen samples were mixed with 0.5 ml of Tadalafil solutions at varying concentrations (0.2, 0.1, 0.05, and 0.025 μg ml-1, respectively). After two hours of incubation, samples treated with 0.2 μg ml-1 Tadalafil demonstrated a significant increase in sperm motility in both groups [2].

The Tadalafil-treated group's erectile function (intocavernosal pressure/mean arterial pressure) at 0.3, 0.5, 1, 3, and 5 Hz was higher than the diabetic group's values at comparable frequencies that were near to the control values [3]. Orally administer 20 mg of Tadalafil or 100 mg of Sildenafil. In neither group were there statistically significant variations in the parameters of computer-assisted semen analysis. After taking sildenafil for one hour and tadalafil for two hours, there was no discernible change in the frequency of acrosome preterm response [2].

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Diabetic rats demonstrated dilated cavernous spaces, smooth muscles with heterochromatic nuclei, degenerated mitochondria, vacuolated cytoplasm, and negative smooth muscle immunoreactivity. Nerve fibers demonstrated a thick myelin sheath and intra-axonal edema, where blood capillaries exhibited thick basement membrane. Diabetic rats on Td showed improved cavernous organization with significant morphometric increases in the area percentage of smooth muscles and elastic tissue and a significant decrease of fibrous tissue. The Td-treated group showed enhanced erectile function (intracavernosal pressure/mean arterial pressure) at 0.3, 0.5, 1, 3, and 5 Hz compared with diabetic group values at the respective frequencies (P <.05) that approached control values. Conclusion: Chronic low-dose administration of Td in diabetic rats is associated with substantial improvement of the structure of penile cavernous tissue, with increased smooth muscles and elastic tissue, decreased fibrous tissue, and functional enhancement of the erectile function. This raises the idea that the change in penile architecture with Td treatment improves erectile function beyond its half-life and its direct pharmacologic action on phosphodiesterase type 5.[3]

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For in vivo part, oral administration of tadalafil (20 mg) or sildenafil (100 mg) was given. In both groups, computer-assisted semen analysis parameters showed no significant difference. After the administration of tadalafil (2 h) and sildenafil (1 h), there was no significant difference observed in premature acrosome reaction incidence rate. Taking both in vitro and in vivo results into consideration, acute on-demand administration of tadalafil would have no adverse effect on semen parameters[2].

Sildenafil, tadalafil, and vardenafil each competitively inhibit cGMP hydrolysis by phosphodiesterase-5 (PDE5), thereby fostering cGMP accumulation and relaxation of vascular smooth muscle. Biochemical potencies (affinities) of these compounds for PDE5 determined by IC(50), K(D) (isotherm), K(D) (dissociation rate), and K(D) ((1/2) EC(50)), respectively, were the following: sildenafil (3.7 +/- 1.4, 4.8 +/- 0.80, 3.7 +/- 0.29, and 11.7 +/- 0.70 nM), tadalafil (1.8 +/- 0.40, 2.4 +/- 0.60, 1.9 +/- 0.37, and 2.7 +/- 0.25 nM); and vardenafil (0.091 +/- 0.031, 0.38 +/- 0.07, 0.27 +/- 0.01, and 0.42 +/- 0.10 nM). Thus, absolute potency values were similar for each inhibitor, and relative potencies were vardenafil >> tadalafil > sildenafil. Binding of each (3)H inhibitor to PDE5 was specific as determined by effects of unlabeled compounds. (3)H Inhibitors did not bind to isolated PDE5 regulatory domain. Close correlation of EC(50) values using all three (3)H inhibitors competing against one another indicated that each occupies the same site on PDE5. Studies of sildenafil and vardenafil analogs demonstrated that higher potency of vardenafil is caused by differences in its double ring. Exchange-dissociation studies revealed two binding components for each inhibitor. Excess unlabeled inhibitor did not significantly affect (3)H inhibitor dissociation after infinite dilution, suggesting the absence of subunit-subunit cooperativity. cGMP addition increased binding affinity of [(3)H]tadalafil or [(3)H]vardenafil, an effect presumably mediated by cGMP binding to PDE5 allosteric sites, implying that either inhibitor potentiates its own binding to PDE5 in intact cells by elevating cGMP. Without inhibitor present, cGMP accumulation would stimulate cGMP degradation, but with inhibitor present, this negative feedback process would be blocked[1].

In vitro[2]
Ten normozoospermic patients and ten asthenozoospermic patients were randomly picked up from our andrological outpatient department respectively. Normozoospermic samples were defined according to the guidelines of World Health Organization (1999): sperm count >20 × 106 ml 1−1, sperm motility >70 per cent, abnormal sperm morphology <70 per cent, vitality >75 per cent and leucocytes<106 ml 1−1. Enrolled patients (age ranged from 26 to 40 years) underwent detailed medical history and physical examination. Patients receiving PDE5 inhibitor treatment, with chronic prostatitis, leucocytospermia or varicocele were excluded.
Every participant was asked to keep sexual abstinence for 4–6 days and to refrain from caffeine, alcohol or nicotine-containing agents 12 h before attendance. Ejaculates were obtained by masturbation into a dry wide-mouth sterile plastic container between 8 and 10 AM in the morning. Immediately after liquefaction, routine semen analyses were performed according to WHO recommendations to obtain initial results.
Samples were then divided into six equal volumes (0.5 ml each) in 3-ml falcon tubes. One was kept as blank control, and one was added with 1 mg ml−1 pentoxifylline as positive control (Nassar et al., 1999). For the other tubes, 0.5 ml tadalafil solutions with different concentrations were added (0.2, 0.1, 0.05 and 0.025 μg ml−1, respectively). Tadalafil solutions were prepared by dissolving its powder in normal saline, and the maximum concentration (0.2 μg ml−1) was determined by the maximum semen content, 2 h after 20 mg tadalafil intake (the maximum recommended dose). Pentoxifylline solution was prepared by adding its parenteral solution (100 mg 5 ml−1) into 95 ml−1 normal saline to reach a final concentration of 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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: 30% propylene glycol, 5% Tween 80, 65% D5W:30 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)