Tadalafil (original) (raw)

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Summary

Tadalafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension.

Brand Names

Adcirca, Alyq, Cialis, Entadfi, Tadliq

Generic Name

Tadalafil

DrugBank Accession Number

DB00820

Background

Tadalafil is a selective phosphodiesterase-5 inhibitor that is used in the treatment of erectile dysfunction (ED), pulmonary arterial hypertension (PAH), and benign prostatic hypertrophy.8,9 It was first approved in 2003 by the FDA for use in ED and later in 2009 for PAH. In contrast to other PDE5 inhibitors like sildenafil, tadalafil has greater selectivity for PDE5 and a longer half-life which has made it a more suitable option for chronic once-daily dosing in the treatment of PAH.2

Type

Small Molecule

Groups

Approved, Investigational

Structure

Weight

Average: 389.404
Monoisotopic: 389.137556111

Chemical Formula

C22H19N3O4

Synonyms

• (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
• (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
• Tadalafil
• Tadalafilo

External IDs

• GF 196960
• IC-351
• IC351
• ICOS 351

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).7,11 It is also indicated for the treatment of pulmonary arterial hypertension (PAH) both alone and in combination with macitentan or other endothelin-1 antagonists.8,9,12

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Associated Conditions

Contraindications & Blackbox Warnings

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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.2,3 Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries.3 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.4 The decreased affinity of tadalafil for PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side effects.8,9,2

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. 7 Patients may experience ED due to a variety of causes including psychogenic, neurogenic, vasculogenic, iatrogenic, or endocrine. 6 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).2,3 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.3 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.7 BPH produces urinary dysfunction through hyperproliferation of the epithelial and smooth muscle layers of the prostate.4 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.8,9,2

Absorption

Tadalafil has a tmax of 0.5-6h with a median of 2h in healthy adults. 1,7 The tmax in adults with PAH is reported as 2-8h with a median of 4h.8 There does not appear to be a significant effect on absorption when tadalafil is taken with food.1

Volume of distribution

Tadalafil has a mean apparent volume of distribution of 63L in healthy adults.1,7 The mean apparent volume of distribution is reported as 77L in adults with PAH.8

Protein binding

Tadalafil is 94% bound to plasma proteins.1,7,8

Metabolism

Tadalafil undergoes hepatic metabolism via CYP3A4 to a catechol metabolite.1,5,7,8 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.

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Route of elimination

Tadalafil is primarily eliminated via hepatic metabolism.1,7,8 These metabolites are mainly excreted in the feces (61%) and to a lesser extent in the urine (36%)

Half-life

The mean half-life of elimination of tadalafil is 15-17.5h in healthy adults.1,7,8 The mean half-life of elimination in adults with PAH is reported as 35h.8

Clearance

The mean apparent oral clearance of tadalafil is 2.5-3.4L/h in healthy adults.1,7,8 The mean apparent oral clearance in adults with PAH is reported as 3.5L/h

Adverse Effects

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Toxicity

Symptoms of overdose are expected to be similar to typical adverse effects which may include headache, dyspepsia, back pain, myalgia, nasopharyngitis, and dizziness.7,8 Standard supportive care is recommended. Hemodialysis is not expected to contribute significantly to tadalafil clearance.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Food Interactions

• Avoid excessive or chronic alcohol consumption. Ingesting excess amounts of alcohol (more than four drinks in a short time) may potentiate the hypotension and dizziness caused by tadalafil.
• Avoid grapefruit products. Tadalafil is metabolized by CYP3A4, and grapefruit products are CYP3A4 inhibitors; therefore, coadministration may increase serum levels of tadalafil and result in increased hypotension.
• Take with or without food.

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Product Images

Brand Name Prescription Products

Generic Prescription Products

Mixture Products

ATC Codes

G04BE08 — Tadalafil

• G04BE — Drugs used in erectile dysfunction
• G04B — UROLOGICALS
• G04 — UROLOGICALS
• G — GENITO URINARY SYSTEM AND SEX HORMONES C02KX52 — Ambrisentan and tadalafil
• C02KX — Antihypertensives for pulmonary arterial hypertension
• C02K — OTHER ANTIHYPERTENSIVES
• C02 — ANTIHYPERTENSIVES
• C — CARDIOVASCULAR SYSTEM G04CB51 — Finasteride and tadalafil
• G04CB — Testosterone-5-alpha reductase inhibitors
• G04C — DRUGS USED IN BENIGN PROSTATIC HYPERTROPHY
• G04 — UROLOGICALS
• G — GENITO URINARY SYSTEM AND SEX HORMONES G04CA54 — Tamsulosin and tadalafil
• G04CA — Alpha-adrenoreceptor antagonists
• G04C — DRUGS USED IN BENIGN PROSTATIC HYPERTROPHY
• G04 — UROLOGICALS
• G — GENITO URINARY SYSTEM AND SEX HORMONES C02KX54 — Macitentan and tadalafil
• C02KX — Antihypertensives for pulmonary arterial hypertension
• C02K — OTHER ANTIHYPERTENSIVES
• C02 — ANTIHYPERTENSIVES
• C — CARDIOVASCULAR SYSTEM

Drug Categories

• 5-alpha Reductase Inhibitors
• Antihypertensive Agents
• Antihypertensives for Pulmonary Arterial Hypertension
• Carbolines
• Cardiovascular Agents
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Drugs that are Mainly Renally Excreted
• Drugs Used in Benign Prostatic Hypertrophy
• Drugs Used in Erectile Dysfunction
• Enzyme Inhibitors
• Genito Urinary System and Sex Hormones
• Genitourinary Agents
• Heterocyclic Compounds, Fused-Ring
• Indole Alkaloids
• Indoles
• Phosphodiesterase 5 Inhibitors
• Phosphodiesterase Inhibitors
• Pyridines
• Urological Agents
• Urologicals
• Vasodilating Agents

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as beta carbolines. These are compounds containing a 9H-pyrido[3,4-b]indole moiety.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Indoles and derivatives

Sub Class

Pyridoindoles

Direct Parent

Beta carbolines

Alternative Parents

3-alkylindoles / Alpha amino acids and derivatives / Benzodioxoles / 2,5-dioxopiperazines / N-methylpiperazines / Benzenoids / Tertiary carboxylic acid amides / Pyrroles / Heteroaromatic compounds / Lactams / Oxacyclic compounds / Acetals / Azacyclic compounds / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Organonitrogen compounds / Organopnictogen compounds show 8 more

Substituents

1,4-diazinane / 2,5-dioxopiperazine / 3-alkylindole / Acetal / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzodioxole / Beta-carboline / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Dioxopiperazine / Heteroaromatic compound / Hydrocarbon derivative / Indole / Lactam / N-alkylpiperazine / N-methylpiperazine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Piperazine / Pyrrole / Tertiary carboxylic acid amide show 20 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

benzodioxoles, pyrazinopyridoindole (CHEBI:71940)

Affected organisms

• Humans and other mammals

UNII

742SXX0ICT

CAS number

171596-29-5

InChI Key

WOXKDUGGOYFFRN-IIBYNOLFSA-N

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

IUPAC Name

(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

SMILES

[H][C@]12CC3=C(NC4=CC=CC=C34)[C@H](N1C(=O)CN(C)C2=O)C1=CC2=C(OCO2)C=C1

Synthesis Reference

Ben-Zion Dolitzky, Dov Diller, "Preparation of tadalafil intermediates." U.S. Patent US20060276652, issued December 07, 2006.

US20060276652

General References

1. Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE, Mitchell MI: Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006 Mar;61(3):280-8. doi: 10.1111/j.1365-2125.2005.02553.x. [Article]
2. Andersson KE: PDE5 inhibitors - pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018 Jul;175(13):2554-2565. doi: 10.1111/bph.14205. Epub 2018 Apr 25. [Article]
3. Arif SA, Poon H: Tadalafil: a long-acting phosphodiesterase-5 inhibitor for the treatment of pulmonary arterial hypertension. Clin Ther. 2011 Aug;33(8):993-1004. doi: 10.1016/j.clinthera.2011.06.008. Epub 2011 Jul 16. [Article]
4. Monica FZ, De Nucci G: Tadalafil for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother. 2019 Jun;20(8):929-937. doi: 10.1080/14656566.2019.1589452. Epub 2019 Mar 22. [Article]
5. Dalvie D, Obach RS, Kang P, Prakash C, Loi CM, Hurst S, Nedderman A, Goulet L, Smith E, Bu HZ, Smith DA: Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites. Chem Res Toxicol. 2009 Feb;22(2):357-68. doi: 10.1021/tx8004357. [Article]
6. Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb S, Maggi M, Nelson CJ, Parish S, Salonia A, Tan R, Mulhall JP, Hellstrom WJ: Erectile dysfunction. Nat Rev Dis Primers. 2016 Feb 4;2:16003. doi: 10.1038/nrdp.2016.3. [Article]
7. FDA Approved Drug Products: Cialis (tadalafil) tablets [Link]
8. FDA Approved Drug Products: Adcirca (tadalafil) tablets [Link]
9. DPD Approved Drug Products: Opsynvi (tadalafil/macitentan) combination tablets [Link]
10. Medisca: Tadalafil MSDS [Link]
11. FDA Approved Drug Products: Entadfi (finasteride/tadalafil) capsules for oral use [Link]
12. FDA Approved Drug Products: Opsynvi (macitentan and tadalafil) tablets for oral use [Link]

External Links

Human Metabolome Database

HMDB0014958

KEGG Drug

D02008

PubChem Compound

110635

PubChem Substance

46507646

ChemSpider

99301

BindingDB

14777

RxNav

358263

ChEBI

71940

ChEMBL

CHEMBL779

ZINC

ZINC000003993855

Therapeutic Targets Database

DAP000615

PharmGKB

PA10333

PDBe Ligand

CIA

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

PDRhealth

PDRhealth Drug Page

Wikipedia

Tadalafil

PDB Entries

1udu / 1xoz

FDA label

MSDS

Clinical Trials

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Manufacturers

• Eli lilly co
• Eli lilly and co
• Eli Lilly and Company

Packagers

• A-S Medication Solutions LLC
• Bryant Ranch Prepack
• Diversified Healthcare Services Inc.
• Eli Lilly & Co.
• Lake Erie Medical and Surgical Supply
• Lilly Del Caribe Inc.
• Nucare Pharmaceuticals Inc.
• Physicians Total Care Inc.
• Rebel Distributors Corp.
• Redpharm Drug
• Southwood Pharmaceuticals
• United Therapeutics Corp.

Dosage Forms

Prices

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA2379948	No	2008-03-25	2020-04-26
CA2181377	No	2002-05-28	2015-01-19
US6140329	No	2000-10-31	2016-07-11
US6821975	Yes	2004-11-23	2021-05-19
US6943166	Yes	2005-09-13	2020-10-26
US7182958	Yes	2007-02-27	2020-10-26
US5859006	Yes	1999-01-12	2018-05-21
US8268847	No	2012-09-18	2029-04-18
US7094781	No	2006-08-22	2022-10-12
US10946015	No	2021-03-16	2026-11-25
US11382917	No	2018-12-24	2038-12-24
US11666576	No	2018-12-24	2038-12-24
US11975006	No	2018-12-24	2038-12-24

State

Solid

Experimental Properties

Predicted Properties

Predicted ADMET Features

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Mass Spec (NIST)

Not Available

Spectra

Chromatographic Properties

Collision Cross Sections (CCS)

Targets

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Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:15489334, PubMed:9714779). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334).

Specific Function

3',5'-cyclic-AMP phosphodiesterase activity

Gene Name

PDE5A

Uniprot ID

O76074

Uniprot Name

cGMP-specific 3',5'-cyclic phosphodiesterase

Molecular Weight

99984.14 Da

References

1. Curran M, Keating G: Tadalafil. Drugs. 2003;63(20):2203-12; discussion 2213-4. [Article]
2. Eardley I, Cartledge J: Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract. 2002 May;56(4):300-4. [Article]
3. Montorsi F, Salonia A, Deho' F, Cestari A, Guazzoni G, Rigatti P, Stief C: Pharmacological management of erectile dysfunction. BJU Int. 2003 Mar;91(5):446-54. [Article]
4. Rotella DP: Tadalafil Lilly ICOS. Curr Opin Investig Drugs. 2003 Jan;4(1):60-5. [Article]
5. Zoraghi R, Francis SH, Corbin JD: Critical amino acids in phosphodiesterase-5 catalytic site that provide for high-affinity interaction with cyclic guanosine monophosphate and inhibitors. Biochemistry. 2007 Nov 27;46(47):13554-63. Epub 2007 Nov 3. [Article]
6. Blount MA, Beasley A, Zoraghi R, Sekhar KR, Bessay EP, Francis SH, Corbin JD: 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. doi: 10.1124/mol.66.1.144. [Article]
7. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
8. FDA Approved Drug Products: Adcirca (tadalafil) tablets [Link]
9. FDA Approved Drug Products: Cialis (tadalafil) tablets [Link]

Kind

Protein

Organism

Humans

Pharmacological action

No

Actions

Inhibitor

General Function

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP (PubMed:10725373, PubMed:10906126, PubMed:11050148, PubMed:16330539). Catalyzes the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'-GMP, respectively (PubMed:10725373, PubMed:10906126, PubMed:11050148).

Specific Function

3',5'-cyclic-AMP phosphodiesterase activity

Gene Name

PDE11A

Uniprot ID

Q9HCR9

Uniprot Name

Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A

Molecular Weight

104750.64 Da

References

1. Weeks JL 2nd, Corbin JD, Francis SH: Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond. J Pharmacol Exp Ther. 2009 Oct;331(1):133-41. doi: 10.1124/jpet.109.156935. Epub 2009 Jul 29. [Article]
2. Weeks JL 2nd, Zoraghi R, Francis SH, Corbin JD: N-Terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is involved in oligomerization. Biochemistry. 2007 Sep 11;46(36):10353-64. Epub 2007 Aug 16. [Article]
3. Andersson KE: PDE5 inhibitors - pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018 Jul;175(13):2554-2565. doi: 10.1111/bph.14205. Epub 2018 Apr 25. [Article]
4. FDA Approved Drug Products: Adcirca (tadalafil) tablets [Link]
5. FDA Approved Drug Products: Cialis (tadalafil) tablets [Link]

Kind

Protein

Organism

Humans

Pharmacological action

No

Actions

Inhibitor

General Function

Participates in processes of transmission and amplification of the visual signal. cGMP-PDEs are the effector molecules in G-protein-mediated phototransduction in vertebrate rods and cones.

Specific Function

3',5'-cyclic-GMP phosphodiesterase activity

Gene Name

PDE6G

Uniprot ID

P18545

Uniprot Name

Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma

Molecular Weight

9643.09 Da

References

1. Andersson KE: PDE5 inhibitors - pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018 Jul;175(13):2554-2565. doi: 10.1111/bph.14205. Epub 2018 Apr 25. [Article]
2. FDA Approved Drug Products: Adcirca (tadalafil) tablets [Link]
3. FDA Approved Drug Products: Cialis (tadalafil) tablets [Link]

Enzymes

Kind

Protein

Organism

Humans

Pharmacological action

No

Actions

Substrate

General Function

A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981).

Specific Function

1,8-cineole 2-exo-monooxygenase activity

Gene Name

CYP3A4

Uniprot ID

P08684

Uniprot Name

Cytochrome P450 3A4

Molecular Weight

57342.67 Da

References

1. Takahiro R, Nakamura S, Kohno H, Yoshimura N, Nakamura T, Ozawa S, Hirono K, Ichida F, Taguchi M: Contribution of CYP3A isoforms to dealkylation of PDE5 inhibitors: a comparison between sildenafil N-demethylation and tadalafil demethylenation. Biol Pharm Bull. 2015;38(1):58-65. doi: 10.1248/bpb.b14-00566. [Article]
2. Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE, Mitchell MI: Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006 Mar;61(3):280-8. doi: 10.1111/j.1365-2125.2005.02553.x. [Article]
3. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
4. FDA Approved Drug Products: Adcirca (tadalafil) tablets [Link]
5. FDA Approved Drug Products: Cialis (tadalafil) tablets [Link]
6. Tadalafil FDA label [File]

Drug created at June 13, 2005 13:24 / Updated at September 29, 2024 12:43