TACROLIMUS

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C44H69NO12.H2O
Molecular Weight	822.0334
Optical Activity	( - )
Defined Stereocenters	14 / 14
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

SMILES

O.[H][C@]1(CC[C@@H](O)[C@@H](C1)OC)\C=C(/C)[C@@]2([H])OC(=O)[C@]3([H])CCCCN3C(=O)C(=O)[C@]4(O)O[C@@]([H])([C@H](C[C@H]4C)OC)[C@H](C[C@@H](C)C\C(C)=C\[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)OC

InChI

InChIKey=NWJQLQGQZSIBAF-MLAUYUEBSA-N

InChI=1S/C44H69NO12.H2O/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;1H2/b25-19+,27-21+;/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+;/m0./s1

HIDE SMILES / InChI

Molecular Formula	C44H69NO12
Molecular Weight	804.0182
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	14 / 14
E/Z Centers	1
Optical Activity	UNSPECIFIED

Molecular Formula	H2O
Molecular Weight	18.0153
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Tacrolimus, previously known as FK506, is the active ingredient in Prograf. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds 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 inhibited. This effect may prevent 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 (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression). Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants, kidney transplants, heart transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
FK506-binding protein 1A 9	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Organ rejection 2	Preventing		Approved 8,429	PROGRAF
Atopic dermatitis 43	Primary		Phase III 656	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
26 ng/mL	0.2 mg/kg 1 times / day multiple, oral		TACROLIMUS unknown	Homo sapiens
6.2 ng/mL	4 mg 1 times / day multiple, oral		TACROLIMUS unknown	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
372 ng × h/mL	0.2 mg/kg 1 times / day multiple, oral		TACROLIMUS unknown	Homo sapiens
74 ng × h/mL	4 mg 1 times / day multiple, oral		TACROLIMUS unknown	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
0.15 mg/kg 2 times / day steady, oral	unhealthy, 1.9 years (range: 3-15 years) n = 91	Disc. AE: Anemia, Edema lung...
5.2 mg 1 times / day multiple, oral Highest studied dose	unhealthy, adult n = 60
8 mg single, oral Highest studied dose	unhealthy, adult n = 1
0.1 mg/kg 2 times / day multiple, oral Recommended	unhealthy, adult	Other AEs: Infection...
0.02 mg/kg single, intravenous	unhealthy, adult n = 12

Showing 1 to 5 of 6 entries

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AEs

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AE	Significance	Dose	Population
Abnormal liver function tests	Disc. AE	0.15 mg/kg 2 times / day steady, oral	unhealthy, 1.9 years (range: 3-15 years) n = 91
Allergic reaction	Disc. AE	0.15 mg/kg 2 times / day steady, oral	unhealthy, 1.9 years (range: 3-15 years) n = 91
Anemia	Disc. AE	0.15 mg/kg 2 times / day steady, oral	unhealthy, 1.9 years (range: 3-15 years) n = 91
Bilirubinemia	Disc. AE	0.15 mg/kg 2 times / day steady, oral	unhealthy, 1.9 years (range: 3-15 years) n = 91
Diarrhea	Disc. AE	0.15 mg/kg 2 times / day steady, oral	unhealthy, 1.9 years (range: 3-15 years) n = 91

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587	substrate 1,037 inhibitor 1,767	substrate 1,217 inhibitor 1,852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2C19 1,478 CYP2E1 882 UGT1A1 204 UGT1A3 84 UGT1A6 108 UGT1A9 116 UGT2B4 19 UGT2B7 146 UGT2B15 64 UGT1A8 36	CYP3A5 395 CYP1A2 1,054 CYP2A6 543 CYP2B6 664 CYP2C8 693 CYP2E1 667 P-gp 1,537 UGT1A4 347

Drug as perpetrator

Show entries

Target	Modality	Activity
CYP1A2 1,692	inhibitor 3,277	no
CYP2A6 739	inhibitor 3,277	no
CYP2C19 1,553	inhibitor 3,277	no
CYP2C9 1,819	inhibitor 3,277	no
CYP2D6 1,891	inhibitor 3,277	no

Showing 1 to 5 of 15 entries

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Drug as victim

Show entries

Target	Modality	Activity
CYP1A2 1,054	substrate 3,367	no
CYP2A6 543	substrate 3,367	no
CYP2B6 664	substrate 3,367	no
CYP2C8 693	substrate 3,367	no
CYP2C9 1,037	substrate 3,367	no

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PubMed

Show entries

Title	Date	PubMed
Neurotoxicity after orthotopic liver transplantation in cyclosporin A- and FK 506-treated patients.	1994	11271254
Neurological complications in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation.	1994	11271222
Renal complications and development of hypertension in the European study of FK 506 and cyclosporin in primary liver transplant recipients.	1994	11271207
Haemolytic-uraemic syndrome after tacrolimus rescue therapy for cortisone-resistant rejection.	1999 Apr	10328486
FK506-induced leukoencephalopathy in children with organ transplants.	1999 Apr 22	10227644

Showing 1 to 5 of 38 entries

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Patents

Sample Use Guides

In Vivo Use Guide

Dosage in Adult Kidney, Liver, or Heart Transplant Patients: Adult kidney transplant patients (Oral Dosage: daily doses should be administered as two divided doses, every 12 hours): in combination with azathioprine: 0.2 mg/kg/day; in combination with MMF/IL-2 receptor antagonist: 0.1 mg/kg/day. Adult liver transplant patients: 0.10-0.15 mg/kg/day. Adult heart transplant patients: 0.075 mg/kg/day. Prograf (TACROLIMUS) injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Prograf capsules. Prograf injection should be discontinued as soon as the patient can tolerate oral administration of Prograf capsules, usually within 2-3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting dose of Prograf injection is 0.03-0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation. Dosage in Pediatric Liver Transplant Patients: (Oral Dosage): Pediatric liver transplant patients 0.15-0.20 mg/kg/day (daily doses should be administered as two divided doses, every 12 hours)

Route of Administration: Other

In Vitro Use Guide

Tacrolimus at concentration of 0.06 μmol/L could promote collagen induced platelet aggregation, inhibit thrombin induced platelet aggregation, have no effect on ristocetin and vWF induced platelet aggregation function. Tacrolimus at concentration of 120 μmol/L and 240 μmol/L could reduce the platelet mitochondrial membrane potential and induce the expression of apoptosis protein caspase-3. In vitro experimental results showed that high concentration of tacrolimus could lead to platelet apoptosis. But the current therapeutic dose of tacrolimus at 0.06 μmol/L (which is equivalent to 50 ng/ml blood concentration) could have different effects on platelet aggregation function according to different stimulating agents.