Tacrolimus

Identification

Summary

Tacrolimus is a calcineurin inhibitor used to prevent organ transplant rejection and to treat moderate to severe atopic dermatitis.

Brand Names

Advagraf, Astagraf, Envarsus, Modigraf, Prograf, Protopic

Generic Name

Tacrolimus

DrugBank Accession Number

DB00864

Background

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex inhibits calcineurin which inhibits T-lymphocyte signal transduction and IL-2 transcription.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 804.0182
Monoisotopic: 803.481976677
Chemical Formula: C₄₄H₆₉NO₁₂

Synonyms

Anhydrous tacrolimus
Tacrolimus
Tacrolimus anhydrous
Tacrolimus, anhydrous

External IDs

FK-506
FK5
K506

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Pharmacology

Indication

Immediate-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants.⁷ Extended-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving kidney transplants, in combination with other immunosuppressants,^8,9 and may be used in patients converted from immediate-release formulations.⁹

Topical tacrolimus ointment is indicated as second-line therapy for short-term and non-continuous treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical treatments or for whom alternative treatments are not advisable.¹⁰ Both available strengths are indicated in adult patients, while only the lower strength (0.03%) formulation is indicated in pediatric patients between 2 and 15 years of age.¹⁰

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Associated Conditions

Indication Type	Indication	Approval Level	Age Group	Patient Characteristics	Dose Form
Prevention of	Graft-versus-host disease	••• •••••
Treatment of	Graft-versus-host disease	••• •••••
Adjunct therapy in prophylaxis of	Heart transplant rejection	••••••••••••	•••••• •••••••••		•••••••• •••••••• ••• ••••••••••• •••••••••
Adjunct therapy in prophylaxis of	Kidney transplant rejection	••••••••••••	•••••	•• •••• •••••• ••••••••••	••••••• •••••••• •••••••
Adjunct therapy in prophylaxis of	Kidney transplant rejection	••••••••••••	•••••		••••••• •••••••• •••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Tacrolimus acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Tacrolimus has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.

Mechanism of action

The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells.

Target	Actions	Organism
APeptidyl-prolyl cis-trans isomerase FKBP1A	inhibitor	Humans

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

Volume of distribution

2.6 ± 2.1 L/kg [pediatric liver transplant patients]
1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]

Protein binding

~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL.

Metabolism

The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5.^6,7 Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring.⁶ The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus.⁷ In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.⁷

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Tacrolimus

Route of elimination

In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Half-life

The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours.

Clearance

0.040 L/hr/kg [healthy subjects, IV]
0.172 ± 0.088 L/hr/kg [healthy subjects, oral]
0.083 L/hr/kg [adult kidney transplant patients, IV]
0.053 L/hr/kg [adult liver transplant patients, IV]
0.051 L/hr/kg [adult heart transplant patients, IV]
0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients]
0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients]
0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]

Adverse Effects

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Toxicity

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD₅₀=134-194 mg/kg (rat).

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
Multidrug resistance protein 1	---	(T;T) / (G;T)	T Allele (G2677T)	ADR Directly Studied	The presence of this genotype in ABCB1 may indicate an increased risk of drug-induced neurotoxicity when treated with tacrolimus.	Details
Cytochrome P450 3A5	CYP3A5*1	Not Available	Functional gene	Effect Directly Studied	Patients with this genotype in CYP3A5 are extensive metabolizers and require higer doses of tacrolimus to attain the therapeutic effect.	Details

Interactions

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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.

Drug	Interaction
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Abacavir	Tacrolimus may decrease the excretion rate of Abacavir which could result in a higher serum level.
Abametapir	The serum concentration of Tacrolimus can be increased when it is combined with Abametapir.
Abatacept	Tacrolimus may increase the immunosuppressive activities of Abatacept.
Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Tacrolimus.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Tacrolimus.

Food Interactions

Avoid alcohol. Consuming alcohol may increase the rate of tacrolimus release from extended-release formulations.
Avoid grapefruit products.
Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of tacrolimus; therefore, monitoring tacrolimus whole blood trough concentrations may be warranted.
Take at the same time every day.
Take on an empty stomach. Take at least 1 hour before or 2 hours after a meal as coadministration with food decreases the rate and extent of absorption.
Take separate from antacids. Coadministration of tacrolimus with aluminum or magnesium hydroxide antacids may increase the serum levels of tacrolimus, which poses a risk for toxicity.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Tacrolimus hydrate	WM0HAQ4WNM	109581-93-3	NWJQLQGQZSIBAF-MSLXHMNKSA-N

Product Images

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Advagraf	Capsule, extended release	3 mg	Oral	Astellas Pharma Europe Bv	2016-09-07	Not applicable
Advagraf	Capsule, extended release	1 mg	Oral	Astellas Pharma Inc	2008-04-09	Not applicable
Advagraf	Capsule, extended release	0.5 mg	Oral	Astellas Pharma Europe Bv	2016-09-07	Not applicable
Advagraf	Capsule, extended release	1 mg	Oral	Astellas Pharma Europe Bv	2016-09-07	Not applicable
Advagraf	Capsule, extended release	0.5 mg	Oral	Astellas Pharma Europe Bv	2016-09-07	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Ach-tacrolimus	Capsule	1 mg	Oral	Accord Healthcare Inc	2023-09-15	Not applicable
Ach-tacrolimus	Capsule	0.5 mg	Oral	Accord Healthcare Inc	2023-09-21	Not applicable
Ach-tacrolimus	Capsule	5 mg	Oral	Accord Healthcare Inc	2023-09-15	Not applicable
Apo-tacrolimus	Capsule	0.5 mg	Oral	Apotex Corporation	Not applicable	Not applicable
Apo-tacrolimus	Capsule	5 mg	Oral	Apotex Corporation	Not applicable	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Hyaluronic Acid Sodium Salt 1% / Niacinamide 4% / Tacrolimus 0.1%	Tacrolimus hydrate (0.1 g/100g) + Hyaluronic acid (1 g/100g) + Nicotinamide (4 g/100g)	Cream	Topical	Sinceru Florida, LLC	2019-05-01	Not applicable
Hyaluronic Acid Sodium Salt 1% / Tacrolimus 0.1% / Urea 20%	Tacrolimus hydrate (0.1 g/100g) + Sodium hyaluronate (1 g/100g) + Urea (20 g/100g)	Cream	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable
Niacinamide 4% / Tacrolimus 0.03%	Tacrolimus hydrate (0.03 g/100g) + Nicotinamide (4 g/100g)	Ointment	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable
Niacinamide 4% / Tacrolimus 0.1%	Tacrolimus hydrate (0.1 g/100g) + Nicotinamide (4 g/100g)	Ointment	Topical	Sincerus Florida, LLC	2019-05-01	Not applicable
PANOLIMUS 0,5 MG KAPSUL, 50 ADET	Tacrolimus hydrate (0.5 mg)	Capsule	Oral	BİEM İLAÇ SAN. VE TİC. A.Ş.	2013-01-29	Not applicable

Chemical Identifiers

UNII: Y5L2157C4J
CAS number: 104987-11-3
InChI Key: QJJXYPPXXYFBGM-LFZNUXCKSA-N
InChI: InChI=1S/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19+,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1
IUPAC Name: (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0^{4,9}]octacos-18-ene-2,3,10,16-tetrone
SMILES: CO[C@@H]1C[C@@H](CC[C@H]1O)\C=C(/C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@H](C[C@@H](C)C\C(C)=C\[C@@H](CC=C)C(=O)C[C@H](O)[C@H]1C)OC

References

Synthesis Reference

Pan Sup Chang, Hoon Cho, "Water soluble polymer-tacrolimus conjugated compounds and process for preparing the same." U.S. Patent US5922729, issued April, 1997.

US5922729

General References

Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987 Sep;40(9):1249-55. [Article]
Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [Article]
Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [Article]
Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K: Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient. Drug Metab Pharmacokinet. 2006 Apr;21(2):122-5. [Article]
Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. [Article]
Iwasaki K: Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab Pharmacokinet. 2007 Oct;22(5):328-35. [Article]
FDA Approved Drug Products: Prograf (tacrolimus) capsules/granules for oral use and injection for intravenous administration [Link]
FDA Approved Drug Products: Astagraf XL (tacrolimus) extended-release capsules for oral administration [Link]
FDA Approved Drug Products: Envarsus XR (tacrolimus) extended-release tablets for oral use [Link]
FDA Approved Drug Products: Protopic (tacrolimus) topical ointment [Link]

External Links

Human Metabolome Database: HMDB15002
KEGG Drug: D00107
KEGG Compound: C01375
PubChem Compound: 445643
PubChem Substance: 46506004
ChemSpider: 393220
BindingDB: 50030448
RxNav: 235991
ChEBI: 61049
ChEMBL: CHEMBL269732
ZINC: ZINC000169289411
Therapeutic Targets Database: DAP000162
PharmGKB: PA451578
PDBe Ligand: FK5
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Tacrolimus

PDB Entries

1bkf / 1fkf / 1fkj / 1q6i / 1tco / 1yat / 2fke / 2vn1 / 3ihz / 3uf8 …

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FDA label

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MSDS

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Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Basic Science	Immunosuppression / Transplanted Kidney Complication	1
4	Active Not Recruiting	Health Services Research	Liver Transplantation	1
4	Active Not Recruiting	Prevention	Kidney Transplant Failure and Rejection / Kidney Transplant Rejection	1
4	Active Not Recruiting	Prevention	Prophylaxis against liver transplant rejection	1
4	Active Not Recruiting	Supportive Care	Renal Transplant Recipient Patients	1

Pharmacoeconomics

Manufacturers

Astellas pharma us inc
Dr reddys laboratories ltd
Sandoz inc
Watson laboratories inc
Astellas Pharma US

Packagers

Astellas Pharma Inc.
B&B Pharmaceuticals
Cardinal Health
Caremark LLC
Doctor Reddys Laboratories Ltd.
Kaiser Foundation Hospital
Mckesson Corp.
Murfreesboro Pharmaceutical Nursing Supply
Neuman Distributors Inc.
Physicians Total Care Inc.
Rebel Distributors Corp.
Sandoz
Watson Pharmaceuticals

Dosage Forms

Form	Route	Strength
Capsule	Oral	0.75 MG
Capsule	Oral	2 MG
Capsule, extended release	Oral	5 mg
Capsule, extended release	Oral	3 mg
Tablet, film coated, extended release
Tablet, film coated, extended release		3 mg
Capsule, extended release	Oral	1.0 mg
Capsule, extended release	Oral	5.0 mg
Capsule, extended release	Oral	0.5 mg
Capsule, extended release	Oral	1 mg
Ointment	Cutaneous	0.00030 g
Capsule, coated, extended release	Oral	0.5 mg/1
Capsule, coated, extended release	Oral	1 mg/1
Capsule, coated, extended release	Oral	5 mg/1
Ointment	Topical	0.0307 g
Capsule, extended release	Oral	0.500 mg
Capsule, extended release	Oral	1.000 mg
Capsule, extended release	Oral	5.000 mg
Tablet, film coated, extended release		0.5 mg
Tablet, film coated, extended release		1 mg
Tablet, film coated, extended release		2 mg
Tablet, film coated, extended release		5 mg
Tablet	Oral	1 mg
Tablet	Oral	4 mg
Tablet, extended release	Oral	0.75 mg
Tablet, extended release	Oral	1 mg
Tablet, extended release	Oral	4 mg
Tablet, extended release	Oral	0.75 mg/1
Tablet, extended release	Oral	1 mg/1
Tablet, extended release	Oral	4 mg/1
Cream	Topical
Ointment	Cutaneous	0.030 g
Ointment	Topical	0.100 g
Granule	Oral	0.2 mg
Granule	Oral	1 mg
Granule, for suspension	Oral
Ointment	Topical
Capsule	Oral	1.000 mg
Capsule	Oral	1.00 mg
Ointment	Topical	0.030 g
Capsule, gelatin coated	Oral	1 mg/1
Granule, for suspension	Oral	0.2 mg/1
Granule, for suspension	Oral	1 mg/1
Injection, solution	Intravenous	5 mg/1mL
Injection, solution, concentrate	Intravenous; Parenteral	5 MG/ML
Solution	Intravenous	5 mg / mL
Capsule	Oral	0.5 mg
Capsule	Oral	1 mg
Solution		5 mg/1ml
Capsule, coated	Oral	1 mg
Solution	Intravenous	5 mg
Capsule	Oral
Injection, solution, concentrate	Intravenous
Capsule	Oral	5 mg
Injection	Intravenous	5 mg/ml
Capsule, extended release	Oral
Capsule, coated	Oral	5 mg
Ointment	Cutaneous	0.03 %
Ointment	Cutaneous	0.1 %
Ointment	Topical	0.03 %
Ointment	Topical	0.03 % w/w
Ointment	Topical	0.1 %
Ointment	Topical	0.1 % w/w
Ointment	Topical	1 mg/1g
Ointment
Ointment		0.03 %w/w
Ointment	Topical	0.03 g/100g
Ointment		0.1 %w/w
Ointment	Topical	0.10 g/100g
Capsule, extended release	Oral	2 mg
Ointment	Topical	0.1 g
Ointment	Topical	0.03 g
Capsule, gelatin coated	Oral	5 mg
Capsule	Oral	0.5 mg/1
Capsule	Oral	1 mg/1
Capsule	Oral	5 mg/1
Capsule, gelatin coated	Oral	0.5 mg/1
Capsule, gelatin coated	Oral	5 mg/1
Ointment	Topical	0.3 mg/1g
Solution	Topical	0.1 g/100g
Cream	Topical	0.1 g/100g
Capsule, coated	Oral	0.5 mg
Capsule, coated	Oral	100000 mg
Capsule, coated	Oral	500000 mg
Capsule, gelatin coated	Oral	0.5 mg
Capsule, gelatin coated	Oral	1 mg
Ointment		0.03 %
Ointment		0.1 %
Ointment	Topical	30 mg/30g
Ointment	Topical
Ointment	Cutaneous	0.003 g
Kit	Topical
Capsule	Oral	2.500 mg

Prices

Unit description	Cost	Unit
Tacrolimus micronized powder	2800.0USD	g
Protopic 0.1% Ointment 60 gm Tube	255.34USD	tube
Protopic 0.03% Ointment 60 gm Tube	251.17USD	tube
Prograf 5 mg/ml ampule	163.94USD	ml
Protopic 0.03% Ointment 30 gm Tube	132.99USD	tube
Protopic 0.1% Ointment 30 gm Tube	124.42USD	tube
Prograf 5 mg capsule	24.26USD	capsule
Tacrolimus anhydrous 5 mg cap	22.3USD	each
Prograf 1 mg capsule	4.85USD	capsule
Tacrolimus 1 mg capsule	4.64USD	capsule
Tacrolimus anhydrous 1 mg cap	4.46USD	each
Protopic 0.1% ointment	4.17USD	g
Protopic 0.03% ointment	4.09USD	g
Prograf 0.5 mg capsule	2.43USD	capsule
Tacrolimus anhydrous 0.5 mg cap	2.23USD	each

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

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US5665727	No	1997-09-09	2014-09-09
US5260301	No	1993-11-09	2011-02-28
CA2037408	No	2002-12-17	2011-03-01
CA1338491	No	1996-07-30	2013-07-30
US6884433	No	2005-04-26	2019-03-25
US6576259	No	2003-06-10	2019-03-25
US8551522	No	2013-10-08	2019-03-25
US6440458	No	2002-08-27	2019-03-25
US9161907	No	2015-10-20	2024-08-30
US8889186	No	2014-11-18	2024-08-30
US8623411	No	2014-01-07	2024-08-30
US8486993	No	2013-07-16	2024-08-30
US8889185	No	2014-11-18	2024-08-30
US8664239	No	2014-03-04	2028-05-30
US8586084	No	2013-11-19	2024-08-30
US8685998	No	2014-04-01	2028-05-30
US8623410	No	2014-01-07	2024-08-30
US8617599	No	2013-12-31	2024-08-30
US7994214	No	2011-08-09	2024-08-30
US8591946	No	2013-11-26	2024-08-30
US9549918	No	2017-01-24	2028-05-30
US9757362	No	2017-09-12	2024-08-30
US9763920	No	2017-09-19	2024-08-30
US10166190	No	2019-01-01	2028-05-30
US8644239	No	2014-02-04	2028-08-30
US10548880	No	2020-02-04	2024-08-30
US10864199	No	2020-12-15	2028-05-30
US11123331	No	2021-09-21	2028-05-30
US11110081	No	2021-09-07	2028-05-30
US11077096	No	2021-08-03	2024-08-30
US11419823	No	2008-05-30	2028-05-30

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	126 °C	Not Available
water solubility	Insoluble	FDA label
logP	3.3	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00402 mg/mL	ALOGPS
logP	3.19	ALOGPS
logP	5.59	Chemaxon
logS	-5.3	ALOGPS
pKa (Strongest Acidic)	9.96	Chemaxon
pKa (Strongest Basic)	-2.9	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	11	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	178.36 Å²	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	215.62 m³·mol^-1	Chemaxon
Polarizability	87.9 Å³	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	-	0.8264
Blood Brain Barrier	-	0.9659
Caco-2 permeable	-	0.5977
P-glycoprotein substrate	Substrate	0.7862
P-glycoprotein inhibitor I	Inhibitor	0.8687
P-glycoprotein inhibitor II	Inhibitor	0.7974
Renal organic cation transporter	Non-inhibitor	0.8135
CYP450 2C9 substrate	Non-substrate	0.9116
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Substrate	0.7435
CYP450 1A2 substrate	Non-inhibitor	0.8874
CYP450 2C9 inhibitor	Non-inhibitor	0.9053
CYP450 2D6 inhibitor	Non-inhibitor	0.9402
CYP450 2C19 inhibitor	Non-inhibitor	0.8969
CYP450 3A4 inhibitor	Non-inhibitor	0.869
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9807
Ames test	Non AMES toxic	0.6355
Carcinogenicity	Non-carcinogens	0.9422
Biodegradation	Not ready biodegradable	0.9698
Rat acute toxicity	2.7541 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9817
hERG inhibition (predictor II)	Non-inhibitor	0.8733

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

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udi-0100000920-d0843a66279867c7c9c2
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udi-0000000490-d725079da40c00a8c862
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0w2a-0000000910-56616471d8a788733682
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udi-0000000940-51818884019148cdfc90
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0007-2400002910-9a1a0136a9a49f826f93
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01ot-0100008900-de59824129517d0ab664

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	298.5606386	predicted	DarkChem Lite v0.1.0
[M-H]-	288.0633386	predicted	DarkChem Lite v0.1.0
[M-H]-	275.78625	predicted	DeepCCS 1.0 (2019)
[M+H]+	287.6645386	predicted	DarkChem Lite v0.1.0
[M+H]+	277.50998	predicted	DeepCCS 1.0 (2019)
[M+Na]+	286.6385386	predicted	DarkChem Lite v0.1.0
[M+Na]+	283.83893	predicted	DeepCCS 1.0 (2019)

Targets

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Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	1000	N/A	N/A	A29168
IC 50 (nM)	2.3	N/A	N/A	A29170
Ki (nM)	0.4	N/A	N/A	A29169

Details1. Peptidyl-prolyl cis-trans isomerase FKBP1A

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Type i transforming growth factor beta receptor binding
Specific Function: Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevent...
Gene Name: FKBP1A
Uniprot ID: P62942
Uniprot Name: Peptidyl-prolyl cis-trans isomerase FKBP1A
Molecular Weight: 11950.665 Da

References

Labrande C, Velly L, Canolle B, Guillet B, Masmejean F, Nieoullon A, Pisano P: Neuroprotective effects of tacrolimus (FK506) in a model of ischemic cortical cell cultures: role of glutamate uptake and FK506 binding protein 12 kDa. Neuroscience. 2006;137(1):231-9. Epub 2005 Nov 10. [Article]
Masri M, Rizk S, Barbari A, Stephan A, Kamel G, Rost M: An assay for the determination of sirolimus levels in the lymphocyte of transplant patients. Transplant Proc. 2007 May;39(4):1204-6. [Article]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33. [Article]
Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
Lampen A, Christians U, Guengerich FP, Watkins PB, Kolars JC, Bader A, Gonschior AK, Dralle H, Hackbarth I, Sewing KF: Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos. 1995 Dec;23(12):1315-24. [Article]

Details2. Cytochrome P450 3A5

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Oxygen binding
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP3A5
Uniprot ID: P20815
Uniprot Name: Cytochrome P450 3A5
Molecular Weight: 57108.065 Da

References

Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ: Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant. 2003 Apr;3(4):477-83. [Article]
Kamdem LK, Streit F, Zanger UM, Brockmoller J, Oellerich M, Armstrong VW, Wojnowski L: Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 2005 Aug;51(8):1374-81. doi: 10.1373/clinchem.2005.050047. Epub 2005 Jun 10. [Article]
Op den Buijsch RA, Christiaans MH, Stolk LM, de Vries JE, Cheung CY, Undre NA, van Hooff JP, van Dieijen-Visser MP, Bekers O: Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol. 2007 Aug;21(4):427-35. doi: 10.1111/j.1472-8206.2007.00504.x. [Article]
Zheng H, Zeevi A, Schuetz E, Lamba J, McCurry K, Griffith BP, Webber S, Ristich J, Dauber J, Iacono A, Grgurich W, Zaldonis D, McDade K, Zhang J, Burckart GJ: Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol. 2004 Feb;44(2):135-40. doi: 10.1177/0091270003262108. [Article]

Carriers

Details1. Serum albumin

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Toxic substance binding
Specific Function: Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Serum albumin
Molecular Weight: 69365.94 Da

Details2. Alpha-1-acid glycoprotein 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Not Available
Specific Function: Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name: ORM1
Uniprot ID: P02763
Uniprot Name: Alpha-1-acid glycoprotein 1
Molecular Weight: 23511.38 Da

Transporters

Details1. P-glycoprotein 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor
Inducer

General Function: Xenobiotic-transporting atpase activity
Specific Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: Multidrug resistance protein 1
Molecular Weight: 141477.255 Da

References

Schuetz EG, Beck WT, Schuetz JD: Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol. 1996 Feb;49(2):311-8. [Article]
Wandel C, Kim RB, Kajiji S, Guengerich P, Wilkinson GR, Wood AJ: P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies. Cancer Res. 1999 Aug 15;59(16):3944-8. [Article]
Quezada CA, Garrido WX, Gonzalez-Oyarzun MA, Rauch MC, Salas MR, San Martin RE, Claude AA, Yanez AJ, Slebe JC, Carcamo JG: Effect of tacrolimus on activity and expression of P-glycoprotein and ATP-binding cassette transporter A5 (ABCA5) proteins in hematoencephalic barrier cells. Biol Pharm Bull. 2008 Oct;31(10):1911-6. [Article]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

Details2. ATP-binding cassette sub-family A member 5

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Atpase activity, coupled to transmembrane movement of substances
Specific Function: May play a role in the processing of autolysosomes.
Gene Name: ABCA5
Uniprot ID: Q8WWZ7
Uniprot Name: ATP-binding cassette sub-family A member 5
Molecular Weight: 186505.825 Da

References

Quezada CA, Garrido WX, Gonzalez-Oyarzun MA, Rauch MC, Salas MR, San Martin RE, Claude AA, Yanez AJ, Slebe JC, Carcamo JG: Effect of tacrolimus on activity and expression of P-glycoprotein and ATP-binding cassette transporter A5 (ABCA5) proteins in hematoencephalic barrier cells. Biol Pharm Bull. 2008 Oct;31(10):1911-6. [Article]

Details3. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

Kalliokoski A, Niemi M: Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705. doi: 10.1111/j.1476-5381.2009.00430.x. Epub 2009 Sep 25. [Article]

Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:55

Tacrolimus

Identification

Structure for Tacrolimus (DB00864)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

Enzymes

References

References

Carriers

Transporters

References

References

References