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2D Structure
Also known as: Cialis, 171596-29-5, Ic351, Tadanafil, Adcirca, Ic 351
Molecular Formula
C22H19N3O4
Molecular Weight
389.4  g/mol
InChI Key
WOXKDUGGOYFFRN-IIBYNOLFSA-N
FDA UNII
742SXX0ICT

A carboline derivative and PHOSPHODIESTERASE 5 INHIBITOR that is used primarily to treat ERECTILE DYSFUNCTION; BENIGN PROSTATIC HYPERPLASIA and PRIMARY PULMONARY HYPERTENSION.
Tadalafil is a Phosphodiesterase 5 Inhibitor. The mechanism of action of tadalafil is as a Phosphodiesterase 5 Inhibitor.
1 2D Structure

2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione
2.1.2 InChI
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
2.1.3 InChI Key
WOXKDUGGOYFFRN-IIBYNOLFSA-N
2.1.4 Canonical SMILES
CN1CC(=O)N2C(C1=O)CC3=C(C2C4=CC5=C(C=C4)OCO5)NC6=CC=CC=C36
2.1.5 Isomeric SMILES
CN1CC(=O)N2[C@@H](C1=O)CC3=C([C@H]2C4=CC5=C(C=C4)OCO5)NC6=CC=CC=C36
2.2 Other Identifiers
2.2.1 UNII
742SXX0ICT
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Cialis

2. Ic 351

3. Ic-351

4. Ic351

5. Pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione, 6-(1,3- Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6r,12ar)-

2.3.2 Depositor-Supplied Synonyms

1. Cialis

2. 171596-29-5

3. Ic351

4. Tadanafil

5. Adcirca

6. Ic 351

7. Icos 351

8. Ic-351

9. Gf 196960

10. (6r,12ar)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,12,12a-tetrahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4(6h,7h)-dione

11. Tadalafil Mylan

12. Trans-tadalafil

13. Tadalafil(cialis)

14. (6r,12ar)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-(methylenedioxy)phenyl) Pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione

15. (6r-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione

16. Chembl779

17. Nsc-750236

18. Nsc-759172

19. 742sxx0ict

20. Gf-196960

21. Ly-450190

22. (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

23. Chebi:71940

24. Tadalafil [usan]

25. Ly450190

26. Dsstox_cid_26786

27. Dsstox_rid_81904

28. Dsstox_gsid_46786

29. (6r,12ar)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

30. 6-benzo[1,3]dioxol-5-yl-2-methyl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

31. Tadalafil Lilly

32. Smr000466321

33. Cialis (tn)

34. Tildenafil

35. Cas-171596-29-5

36. Hsdb 7303

37. Unii-742sxx0ict

38. Tadalafila

39. Tadalafilo

40. Taldalafil

41. Tadalafil [usan:inn:ban]

42. Tadalafil Solution

43. 1xoz

44. Cialis, Tadalafil

45. Ncgc00168781-01

46. Tadalafil- Bio-x

47. (2r,8r)-2-(1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11,13,15-tetraene-4,7-dione

48. Adcirca (tn)

49. Tadalafil (cialis)

50. Zalutia (tn)

51. (6r,12ar)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione

52. Ks-1117

53. Tadalafil [inn]

54. Tadalafil [jan]

55. Tadalafil [mi]

56. Tadalafil; Cialis

57. Tadalafil [hsdb]

58. Tadalafil [vandf]

59. (-)-tadalafil (6r)

60. Tadalafil [mart.]

61. Tadalafil [usp-rs]

62. Tadalafil [who-dd]

63. Tadalafil (jan/usp/inn)

64. Schembl33333

65. Tadalafil [ema Epar]

66. Mls000759426

67. Mls001165782

68. Mls001195644

69. Mls001424132

70. Mls006010126

71. Tadalafil Specified Impurity A

72. Gtpl7299

73. Tadalafil [orange Book]

74. Dtxsid9046786

75. Tadalafil [ep Monograph]

76. Bdbm14777

77. Tadalafil (6r ,12as)- Lilly

78. Tadalafil [usp Monograph]

79. Entadfi Component Tadalafil

80. Hms2051n17

81. Hms2235l21

82. Hms3884g19

83. Pharmakon1600-01505639

84. Amy10321

85. Ex-a2644

86. Zinc3993855

87. Tox21_112642

88. Hy-90009a

89. Mfcd07771966

90. Nsc750236

91. Nsc759172

92. S1512

93. Tadalafil 1.0 Mg/ml In Acetonitrile

94. Tadalafil 100 Microg/ml In Methanol

95. Tadalafil Component Of Entadfi

96. Akos015892559

97. Tox21_112642_1

98. Ab42193

99. Ccg-100973

100. Cs-1414

101. Db00820

102. Nc00223

103. Nsc 750236

104. Nsc 759172

105. 1,3-benzodioxol-5-yl(methyl)[?]dione

106. Ncgc00263909-02

107. Tadalafil 100 Microg/ml In Acetonitrile

108. (6r,12ar)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

109. Bt164435

110. Gf196960

111. Pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6r,12ar)-

112. Pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6r-trans)-

113. (-)-tadalafil (6r ,12as) Diastereomer

114. Sw197603-2

115. A23556

116. D02008

117. Ab00639969-08

118. Ab00639969_09

119. Ab00639969_10

120. 596t295

121. Ar-270/43507798

122. Q424156

123. Sr-05000001940

124. Sr-05000001940-1

125. Brd-k93645900-001-04-8

126. Tadalafil Solution, 1.0 Mg/ml In Acetonitrile, Ampule Of 1 Ml, Certified Reference Material

127. (2r,8r)-2-(1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione

128. (2r,8r)-2-(2h-1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11(16),12,14-tetraene-4,7-dione

129. (2r,8r)-2-(2h-1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11,13,15-tetraene-4,7-dione

130. (6r,12 Ar)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

131. (6r,12ar) 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino [1',2':1,6] Pyrido[3,4-b]indole-1,4-dione

132. (6r,12ar) 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

133. (6r,12ar)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1,2:1,6]pyrido[3,4-b]indole-1,4-dione

134. (6r,12ar)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1,2,1,6]pyrido[3,4-b]indole-1,4-dione

135. (6r,3,6,7,12,12a-hexahydro-2-methyl-6-[3,4-(methylenedioxy)phenyl]pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

136. 1242099-07-5

137. 171488-03-2

138. 6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione

139. Pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6r-12ar)-

140. Pyrazino[1',6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12ahexahydro-2-methyl-, (6r,12ar)-

141. Rel-(6r,12ar)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,12,12a-tetrahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4(6h,7h)-dione

2.4 Create Date
2005-06-24
3 Chemical and Physical Properties
Molecular Weight 389.4 g/mol
Molecular Formula C22H19N3O4
XLogP32.3
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count4
Rotatable Bond Count1
Exact Mass389.13755610 g/mol
Monoisotopic Mass389.13755610 g/mol
Topological Polar Surface Area74.9 Ų
Heavy Atom Count29
Formal Charge0
Complexity702
Isotope Atom Count0
Defined Atom Stereocenter Count2
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 6  
Drug NameAdcirca
PubMed HealthTadalafil (By mouth)
Drug ClassesAntihypertensive, Erectile Dysfunction Agent
Drug LabelADCIRCA (tadalafil), an oral treatment for pulmonary arterial hypertension, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a mo...
Active IngredientTadalafil
Dosage FormTablet
RouteOral
Strength20mg
Market StatusPrescription
CompanyEli Lilly

2 of 6  
Drug NameCialis
PubMed HealthTadalafil (By mouth)
Drug ClassesAntihypertensive, Erectile Dysfunction Agent
Drug LabelCIALIS (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is: The ch...
Active IngredientTadalafil
Dosage FormTablet
RouteOral
Strength2.5mg; 5mg; 10mg; 20mg
Market StatusPrescription
CompanyLilly

3 of 6  
Drug NameTadalafil
PubMed HealthTadalafil (By mouth)
Drug ClassesAntihypertensive, Erectile Dysfunction Agent
Drug LabelCIALIS (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is: The ch...
Active IngredientTadalafil
Dosage FormTablet
Routeoral
Strength20mg
Market StatusTentative Approval
CompanySynthon Pharms

4 of 6  
Drug NameAdcirca
PubMed HealthTadalafil (By mouth)
Drug ClassesAntihypertensive, Erectile Dysfunction Agent
Drug LabelADCIRCA (tadalafil), an oral treatment for pulmonary arterial hypertension, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a mo...
Active IngredientTadalafil
Dosage FormTablet
RouteOral
Strength20mg
Market StatusPrescription
CompanyEli Lilly

5 of 6  
Drug NameCialis
PubMed HealthTadalafil (By mouth)
Drug ClassesAntihypertensive, Erectile Dysfunction Agent
Drug LabelCIALIS (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is: The ch...
Active IngredientTadalafil
Dosage FormTablet
RouteOral
Strength2.5mg; 5mg; 10mg; 20mg
Market StatusPrescription
CompanyLilly

6 of 6  
Drug NameTadalafil
PubMed HealthTadalafil (By mouth)
Drug ClassesAntihypertensive, Erectile Dysfunction Agent
Drug LabelCIALIS (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is: The ch...
Active IngredientTadalafil
Dosage FormTablet
Routeoral
Strength20mg
Market StatusTentative Approval
CompanySynthon Pharms

4.2 Therapeutic Uses

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

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


4.3 Drug Warning

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.

US FDA; FDA Statement. FDA Updates Labeling for Viagra, Cialis and Levitra for Rare Post-Marketing Reports of Eye Problems (July 8, 2005) Available from, as of July 12, 2005: https://www.fda.gov/bbs/topics/NEWS/2005/NEW01201.html


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.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


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.

Physicians Desk Reference. 58th ed. Thomson PDR. Montvale, NJ 2004.


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.

Physicians Desk Reference. 58th ed. Thomson PDR. Montvale, NJ 2004.


For more Drug Warnings (Complete) data for TADALAFIL (18 total), please visit the HSDB record page.


4.4 Drug Indication

Tadalafil is indicated for the treatment of erectile dysfunction (ED) and either alone or in combination with [finasteride] for the treatment of benign prostatic hypertrophy (BPH). It is also indicated for the treatment of pulmonary arterial hypertension (PAH) both alone and in combination with [macitentan] or other endothelin-1 antagonists.


FDA Label


Adcirca is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as World Health Organization functional class II and III, to improve exercise capacity (see section 5. 1).

Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.


Treatment of erectile dysfunction.

In order for tadalafil to be effective, sexual stimulation is required.

Cialis is not indicated for use by women.


Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective, sexual stimulation is required.

Tadalafil Lilly is not indicated for use by women.

Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.


Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective, sexual stimulation is required.

Tadalafil Mylan is not indicated for use by women.


Talmanco is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.


Treatment of pulmonary arterial hypertension


5 Pharmacology and Biochemistry
5.1 Pharmacology

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.


5.2 MeSH Pharmacological Classification

Vasodilator Agents

Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)


Phosphodiesterase 5 Inhibitors

Compounds that specifically inhibit PHOSPHODIESTERASE 5. (See all compounds classified as Phosphodiesterase 5 Inhibitors.)


Urological Agents

Drugs used in the treatment of urological conditions and diseases such as URINARY INCONTINENCE and URINARY TRACT INFECTIONS. (See all compounds classified as Urological Agents.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
TADALAFIL
5.3.2 FDA UNII
742SXX0ICT
5.3.3 Pharmacological Classes
Phosphodiesterase 5 Inhibitors [MoA]; Phosphodiesterase 5 Inhibitor [EPC]
5.4 ATC Code

G04BE08


G04BE08


G04BE08


G04BE08


G04BE08


G04BE08

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355


G - Genito urinary system and sex hormones

G04 - Urologicals

G04B - Urologicals

G04BE - Drugs used in erectile dysfunction

G04BE08 - Tadalafil


5.5 Absorption, Distribution and Excretion

Absorption

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.


Route of Elimination

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%)


Volume of Distribution

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.


Clearance

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.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


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.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


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.

Physicians Desk Reference. 58th ed. Thomson PDR. Montvale, NJ 2004.


Elimination: Mean oral clearance: 2.5 L per hour. Fecal: 61%. Urine: 36%.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


For more Absorption, Distribution and Excretion (Complete) data for TADALAFIL (11 total), please visit the HSDB record page.


5.6 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.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


5.7 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

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


5.8 Mechanism of Action

Tadalafil is a selective phosphodiesterase-5 (PDE5) inhibitor that produces several downstream effects with the most common therapeutic effect being smooth muscle relaxation. Patients may experience ED due to a variety of causes including psychogenic, neurogenic, vasculogenic, iatrogenic, or endocrine. These causes result in dysfunction of penile smooth muscle relaxation through either disrupted neuronal signaling or direct influence on smooth muscle cells. During sexual arousal, non-adrenergic non-cholinergic (NANC) neurons release nitric oxide (NO). Nitric oxide stimulates guanylate cyclase which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). cGMP activates the cGMP-dependent kinase (PKG) in a signal cascade which activates K+ channels leading to inhibition of Ca2+ channels, inhibits platelet activation, and inhibits smooth muscle cell proliferation while inducing apoptosis. This signal cascade is attenuated by PDE5 which breaks the phosphodiester bond of cGMP, converting it to GMP. Inhibition of PDE5 by tadalafil increases signaling via the PKG cascade which supports penile smooth muscle relaxation during sexual arousal by decreasing Ca2+ entry into smooth muscle cells. This smooth muscle relaxation allows blood to fill the corpus cavernosum thereby producing an erection. In PAH, blood pressure in the pulmonary arteries is raised due to a variety of mechanisms stemming from endothelial dysfunction. Decreased production of NO and prostacyclin reduce vasodilatory signaling while overproduction of endothelin-1 and thromboxane increase vasoconstriction. Inflammation, thromboses, and hypoxia later contribute to vascular remodeling which further reduces luminal size. The resultant increase in blood pressure reduces the capacity for gas exchange and increases afterload at the right ventricle, producing symptoms of dyspnea, fatigue, and dizziness as well as leading to right-sided heart failure. Tadalafil exerts its therapeutic effect in PAH through boosting NO-cGMP signaling to contribute to smooth muscle relaxation as with ED. Lastly, tadalafil is used to treat BPH. BPH produces urinary dysfunction through hyperproliferation of the epithelial and smooth muscle layers of the prostate. The increased size of the prostate blocks urine flow through the urethra resulting in higher residual volumes due to incomplete emptying. Tadalafil does not appear to exert its benefit via smooth muscle relaxation of the prostate. It may instead exert its effect through a mix of increased oxygenation and decreased inflammation, which decreases tissue remodeling, and inhibition of cell proliferation through the cGMP cascade. The decreased affinity for PDE6 compared to other PDE5 inhibitors may explain the decreased incidence of visual side effects as PDE6 is present in the eye and contributes to color vision.


In vitro studies have shown that the effect of tadalafil is more potent on phosphodiesterase type 5 (PDE5) than on other phosphodiesterases. These studies have shown that tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE8, PDE9, PDE10 and 14-fold more potent for PDE5 than for PDE11A1, an enzyme found in human skeletal muscle. Tadalafil inhibits human recombinant PDE11A1 activity at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


Studies in vitro have demonstrated that tadalafil is a selective inhibitor of phosphodiesterase type 5 (PDE5). PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.


Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosum smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic GMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cyclic GMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect on the absence of sexual stimulation.

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.