FKBP12; calcineurin; macrocyclic lactone

Activation of NO synthase, IL-2 gene transcription, cell degranulation, and apoptosis are among the calcium-dependent processes that are inhibited by tacrolimus monohydrate (FK506 monohydrate, Fujimycin monohydrate, FR900506 monohydrate). By binding to FKBPs inside the hormone receptor complex and inhibiting degradation, tacrolimus also increases the effects of progesterone and glucocorticoids. The drug might increase TGFβ-1 gene expression in a manner similar to what has been seen for CsA. Tacrolimus inhibits T cell growth in response to T cell receptor ligation[1]. The treatment of MH3924A cells with a low dosage of Tacrolimus (FK506, 10 μg/L) does not greatly impact their ability to proliferate (P=0.135). Treatment with increasing concentrations of Tacrolimus (100-1,000 μg/L) dramatically increases (P<0.01) the proliferation of MH3924A cells. AMD3100 treatment, at any dose (10, 50, or 100 μg/L), does not appear to affect the proliferation of MH3924A cells (P>0.05). However, the in vitro proliferation of MH3924A cells is boosted (P<0.01)[3] when different doses of AMD3100 are coupled with 100 μg/L Tacrolimus.

Mice treated with Dextran sulfate sodium (DSS) from Days 10 to 16 or 23 are given Tacrolimus to study the therapeutic effect on the progression and maintenance of colitis. In comparison to normal animals, the control group treated with DSS exhibited a substantial reduction in colon length and an increase in colon weight at Days 17 and 24. Furthermore, the control group's colon weight per unit length is more than twice as high as the normal group's. While Tacrolimus treatment for 7 or 14 days considerably suppresses increases in colon weight per unit length in rats treated with DSS as compared to the control group, the colon shortening is not actually restored by this treatment. Furthermore, as indicated by the inhibitory percentages (59% vs. 28%), the inhibitory effect of tacrolimus on increases in colon weight per unit length is more pronounced with a 14-d treatment than a 7-d treatment[4].

Tacrolimus (FK506) inhibits calcium-dependent events, such as IL-2 gene transcription, NO synthase activation, cell degranulation, and apoptosis. Tacrolimus also potentiates the actions of glucocorticoids and progesterone by binding to FKBPs contained within the hormone receptor complex, preventing degradation. The agent may enhance expression of the TGFβ-1 gene in a fashion analogous to that demonstrated for CsA. T cell proliferation in response to ligation of the T cell receptor is inhibited by Tacrolimus. Treatment with a low concentration of Tacrolimus (FK506,10 μg/L) does not significantly affect the proliferation of MH3924A cells (P=0.135). Upon treatment with higher concentrations of Tacrolimus (100-1,000 μg/L), the proliferation of MH3924A cells is significantly enhanced (P<0.01). However, when different concentrations of AMD3100 are combined with 100 μg/L Tacrolimus, the in vitro proliferation of MH3924A cells is increased (P<0.01).

Tacrolimus, formerly known as FK506, is a macrolide antibiotic with immunosuppressive properties. Although structurally unrelated to cyclosporin A (CsA), its mode of action is similar. It exerts its effects principally through impairment of gene expression in target cells. Tacrolimus bonds to an immunophilin, FK506 binding protein (FKBP). This complex inhibits calcineurin phosphatase. The drug inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis. Tacrolimus also potentiates the actions of glucocorticoids and progesterone by binding to FKBPs contained within the hormone receptor complex, preventing degradation. The agent may enhance expression of the transforming growth factor beta-1 gene in a fashion analogous to that demonstrated for CsA. T cell proliferation in response to ligation of the T cell receptor is inhibited by tacrolimus. Type 1 T helper cells appear to be preferentially suppressed compared with type 2 T helper cells. T cell-mediated cytotoxicity is impaired. B cell growth and antibody production are affected indirectly by the suppression of T cell-derived growth factors necessary for these functions. Antigen presentation appears to be spared. The molecular events affected by tacrolimus continue to be discovered[1].

Absorption, Distribution and Excretion
Following oral administration, tacrolimus is not completely absorbed in the gastrointestinal tract, and there is significant individual variability. The absolute bioavailability in adult kidney transplant patients was 17±10%; in adult liver transplant patients, it was 22±6%; and in healthy subjects, it was 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. In 18 fasting healthy volunteers, after a single oral dose of 3, 7, and 10 mg tacrolimus, the peak plasma concentration (Cmax) and area under the curve (AUC) increased proportionally to the dose. Absorption rate and extent were highest when taken on an empty stomach. Meal timing also affects bioavailability. Compared to a fasting state, immediate administration after a meal reduced the average Cmax by 71% and the average AUC by 39%. Administration 1.5 hours after a meal reduced the average Cmax by 63% and the average AUC by 39% compared to a fasting state. In the human body, less than 1% of the administered dose is excreted unchanged in the urine. When administered intravenously, fecal excretion accounted for 92.6±30.7%, and urinary excretion accounted for 2.3±1.1%. 2.6 ± 2.1 L/kg [Pediatric liver transplant patients]
1.07 ± 0.20 L/kg [Patients with renal insufficiency, 0.02 mg/kg/4 hours, intravenous]
3.1 ± 1.6 L/kg [Mild hepatic insufficiency, 0.02 mg/kg/4 hours, intravenous]
3.7 ± 4.7 L/kg [Mild hepatic insufficiency, 7.7 mg, oral]
3.9 ± 1.0 L/kg [Severe hepatic insufficiency, 0.02 mg/kg/4 hours, intravenous]
3.1 ± 3.4 L/kg [Severe hepatic insufficiency, 8 mg, oral]
0.040 L/hr/kg [Healthy subjects, intravenous]
0.172 ± 0.088 L/hr/kg [Healthy subjects, oral]
0.083 L/hr/kg [Adult kidney transplant patient, intravenous injection]
0.053 L/hr/kg [Adult liver transplant patient, intravenous injection]
0.051 L/hr/kg [Adult heart transplant patient, intravenous injection]
0.138 ± 0.071 L/hr/kg [Pediatric liver transplant patient]
0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [Pediatric kidney transplant patient]
0.038 ± 0.014 L/hr/kg [Patients with renal insufficiency, 0.02 mg/kg/4 hours, intravenous injection]
0.042 ± 0.02 L/hr/kg [Mild hepatic impairment, 0.02 mg/kg/4 hours, intravenous injection]
0.034 ± 0.019 L/hr/kg [Mild hepatic impairment, 7.7 mg, oral]
0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hours, intravenous injection]
0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg, oral]
This study aimed to assess the concentration of tacrolimus in breast milk and neonatal exposure during breastfeeding. This observational cohort study was conducted at two tertiary referral high-risk obstetric clinics. The study included 14 women who took tacrolimus during pregnancy and lactation and their 15 infants, 11 of whom were exclusively breastfed. Tacrolimus levels were analyzed using liquid chromatography-tandem mass spectrometry. Maternal and umbilical cord blood samples were collected at delivery, and maternal, infant, and breast milk samples were collected postpartum, where possible. Tacrolimus levels decreased in all infants who underwent continuous sampling, with a daily decrease of approximately 15% (geometric mean concentration ratio 0.85; 95% confidence interval 0.82–0.88; P < 0.001). Tacrolimus levels were not elevated in breastfed infants compared to bottle-fed infants (median 1.3 μg/L [range 0.0–4.0] vs. 1.0 μg/L [range 0.0–2.3]; P = 0.91). The maximum absorption of tacrolimus in breast milk was estimated to be 0.23% of the maternal dose (adjusted for body weight). The amount of tacrolimus ingested by infants through breast milk was negligible. Breastfeeding did not appear to slow the decline in high tacrolimus blood concentrations at birth in infants. Maternal and umbilical cord (venous and arterial) blood samples were collected at delivery from eight solid organ transplant recipients to measure the bound and free concentrations of tacrolimus and its metabolites in blood and plasma. Pharmacokinetics of tacrolimus in breast milk was assessed in one of the subjects. At delivery, the mean concentration (± standard deviation) of tacrolimus in umbilical cord blood was 6.6 ± 1.8 ng/ml, equivalent to 71 ± 18% (range 45–99%) of the maternal concentration (9.0 ± 3.4 ng/ml). The mean concentration (0.09 ± 0.04 ng/ml) and free drug concentration (0.003 ± 0.001 ng/ml) of tacrolimus in umbilical cord plasma were approximately one-fifth of the corresponding maternal concentration. The concentration of tacrolimus in umbilical cord artery blood was 100 ± 12% of the concentration in umbilical cord blood. Furthermore, the infant received less than 0.3% of the mother's weight-adjusted dose of tacrolimus through breast milk. The difference in tacrolimus concentrations between maternal and cord blood may be partly attributed to placental P-gp function, higher erythrocyte distribution, and higher hematocrit in umbilical cord blood. Ten colostrum samples were collected from six women in the early postpartum period (0-3 days), with an average drug concentration of 0.79 ng/mL (range 0.3-1.9 ng/mL). The median ratio of breast milk to maternal plasma was 0.5. Tacrolimus has a plasma protein binding rate of approximately 99%, which is concentration-independent within the range of 5-50 ng/mL. Tacrolimus primarily binds to albumin and α-1-acid glycoprotein and is highly bound to erythrocytes. The distribution of tacrolimus in whole blood and plasma depends on various factors, such as hematocrit, temperature during plasma separation, drug concentration, and plasma protein concentration. In a US study, the average ratio of whole blood concentration to plasma concentration was 35 (range 12-67). Based on blood drug concentrations, there is no evidence that intermittent topical application of tacrolimus for up to one year results in accumulation in the body. As with other topical calcineurin inhibitors, it is currently unclear whether tacrolimus distributes to the lymphatic system. For more complete data on the absorption, distribution, and excretion of tacrolimus (9 metabolites in total), please visit the HSDB record page.

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Metabolism/Metabolites
Tacrolimus metabolism is primarily mediated by CYP3A4, and secondarily by CYP3A5.Tacrolimus is metabolized into eight metabolites: 13-demethyltacrolimus, 31-demethyltacrolimus, 15-demethyltacrolimus, 12-hydroxytacrolimus, 15,31-didemethyltacrolimus, 13,31-didemethyltacrolimus, 13,15-didemethyltacrolimus, and a final metabolite involving O-demethylation and fused ring formation. In human liver microsomal incubation assays, the major metabolite identified was 13-demethyltacrolimus. In vitro studies have shown that the 31-demethyl metabolite has the same activity as tacrolimus. Tacrolimus is primarily metabolized via a mixed-function oxidase system, particularly the cytochrome P-450 system (CYP3A). A metabolic pathway generating eight possible metabolites has been proposed. In vitro experiments have shown that demethylation and hydroxylation are the main biotransformation mechanisms. The major metabolite identified in human liver microsomal incubation experiments is 13-demethyltacrolimus. In vitro studies have shown that the 31-demethyl metabolite has the same activity as tacrolimus. Known human metabolites include 13-O-demethyltacrolimus and 15-O-demethyltacrolimus. The elimination half-lives in healthy adult volunteers, kidney transplant recipients, liver transplant recipients, and heart transplant recipients are approximately 35, 19, 12, and 24 hours, respectively. The elimination half-life in pediatric liver transplant patients was 11.5 ± 3.8 hours, and in pediatric kidney transplant patients it was 10.2 ± 5.0 hours (range 3.4–25 hours). In a mass balance study of intravenously administered radiolabeled tacrolimus in 6 healthy volunteers, the elimination half-life calculated based on radioactivity was 48.1 ± 15.9 hours, while the elimination half-life calculated based on tacrolimus concentration was 43.5 ± 11.6 hours. With oral administration, the elimination half-life calculated based on radioactivity was 31.9 ± 10.5 hours, while the elimination half-life calculated based on tacrolimus concentration was 48.4 ± 12.3 hours… This article reports a case of tacrolimus toxicity in a non-transplant patient. The patient received 2.1 mg/kg/day of tacrolimus for 4 consecutive days (therapeutic doses range from 0.03 to 0.05 mg/kg/day). Her tacrolimus elimination half-life was 16.5 hours, while the mean half-life in healthy volunteers was 34.2 ± 7.7 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Limited data suggest that systemically administered tacrolimus is present in low concentrations in breast milk and may not have adverse effects on breastfed infants. Experts and guidelines in the US and Europe generally consider tacrolimus use during lactation to be safe. If this medication is used during lactation, exclusively breastfed infants should be monitored, and serum drug concentrations may be measured if necessary to rule out toxicity.
Topical application of tacrolimus poses a lower risk to breastfed infants because absorption is poor after topical application, with most patients achieving peak plasma concentrations below 2 mcg/L. Ensure that the infant's skin does not come into direct contact with the treated area. Current guidelines allow for topical application of tacrolimus to the nipple immediately after breastfeeding, with the nipple gently cleaned before breastfeeding. Only water-soluble creams or gels should be applied to the breast or nipple, as ointments may expose the infant to high concentrations of mineral oil through licking; therefore, pimecrolimus cream may be superior to tacrolimus ointment for nipple application.
◉ Impact on Breastfed Infants
An infant who was exclusively breastfed from pregnancy until at least 2.5 months of age while the mother was receiving tacrolimus treatment, during which time the infant's physical and neurological development was normal. Ultrasound examination of the infant's thymus was normal.
The National Transplant Pregnancy Registry in the United States reported data collected between 1991 and 2011 on mothers who breastfed after organ transplantation. A total of 68 mothers who received transplants (primarily kidneys or livers) used tacrolimus during breastfeeding, breastfeeding a total of 83 infants. The duration of breastfeeding ranged from 1 week to 1.5 years, and the follow-up period for children ranged from several weeks to 16 years. No problems were reported in any of the infants or children. As of December 2013, 92 mothers had breastfed 125 infants for up to 26 months without any significant adverse events in the infants. Six women who received tacrolimus during pregnancy due to organ transplantation had infants who were breastfed (4 exclusively breastfed, 2 partially breastfed) for 45 to 180 days and were followed up for 2 to 30 months. The average daily tacrolimus dose for these mothers during lactation was 9.6 mg (range 4.5 to 15 mg daily). Four mothers also received azathioprine 100 to 150 mg/day, one received diltiazem, and one received prednisolone 15 mg and aspirin 75 mg/day. No significant tacrolimus-related side effects were observed in any of the infants; one infant experienced transient thrombocytosis, which resolved spontaneously with continued breastfeeding. Developmental milestones were normal, and no infection patterns were observed. Two mothers with systemic lupus erythematosus were reported to have received 3 mg of tacrolimus daily and prednisone 30 or 40 mg daily during pregnancy and lactation. Both children were healthy three years after birth. The duration of breastfeeding was not mentioned. In a 25-year case series of women who underwent liver transplantation, one woman breastfed her infant while taking tacrolimus (duration of feeding was not mentioned). No neonatal complications were observed. A mother who received a liver transplant received monthly beracip 10 mg/kg, daily extended-release tacrolimus (envasopressin and seroxicloxicin), daily azathioprine 25 mg, and daily prednisone 2.5 mg. She breastfed her infant for one year (duration of breastfeeding was not specified). The infant's growth, development, and cognitive milestones were normal. An Australian case series reported three women who received heart transplants and gave birth to five infants, all of whom were breastfed while their mothers were receiving tacrolimus (duration of breastfeeding was not specified). The daily dose ranged from 3 to 13 mg. No adverse events were reported in the infants until discharge.
A woman with rheumatoid arthritis who was unresponsive to etanercept took 200 mg of thalidomide every two weeks during pregnancy until week 37 of gestation. She also took prednisolone 10 mg and tacrolimus 3 mg daily. She delivered a healthy baby at week 38 of gestation and breastfed. She continued taking prednisolone postpartum, restarted tacrolimus 7 days postpartum, and restarted thalidomide 28 days postpartum. The mother continued breastfeeding until 6 months postpartum. The infant received multiple live vaccines, including BCG, at 6 months of age without adverse reactions.
A woman who received a heart transplant took tacrolimus alone throughout her pregnancy and postpartum while breastfeeding her infant (for an unspecified period) for up to one year. The infant had normal weight gain, normal motor development, and showed no signs of metabolic disorders or serious infection. The infant's age at the time of evaluation was not specified.
◉ Effects on Lactation and Breast Milk
A study of kidney transplant patients receiving tacrolimus immunosuppressive therapy found that the median serum prolactin level in women taking tacrolimus was 14.4 mcg/L, compared to 17.6 mcg/L in women not taking tacrolimus. This difference was statistically significant. The median serum testosterone level (0.121 vs 0.137 mcg/L) and serum cortisol level (82.5 vs 105 mg/L) were also significantly lower in the tacrolimus group. The decreased prolactin level may be due to the suppression of human prolactin gene transcription. Not all studies have found that tacrolimus lowers serum prolactin levels. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

[1]. Mode of action of Tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec;17(6):584-91.

[2]. Tacrolimus ameliorates dextran sulfate sodium-induced colitis in mice: implication of interferon-γ and interleukin-1β suppression. Biol Pharm Bull. 2011;34(12):1823-7.

[3]. mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. J Inherit Metab Dis. 2016 Nov;39(6):877-886.

[4]. Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF 1α expression in vivo. Mol Med Rep. 2014 Aug;10(2):585-92.

Tacrolimus hydrate is a monohydrate form of tacrolimus and is an immunosuppressant. It contains anhydrous tacrolimus. Tacrolimus is a macrolide antibiotic isolated from the culture medium of Streptomyces tsukubaensis strains. It has potent immunosuppressive activity in vivo and inhibits T-lymphocyte activation induced by in vitro antigens or mitogens. See also: Tacrolimus (note moved to). Therapeutic Uses Immunosuppressant Pracophora is indicated for organ rejection prophylaxis in patients receiving allogeneic kidney transplants. It is recommended that Pracophora be used in combination with azathioprine or mycophenolate mofetil (MMF) and corticosteroids. /US product label includes/ Pracophora is indicated for organ rejection prophylaxis in patients receiving allogeneic liver transplants. It is recommended that Pracophora be used in combination with corticosteroids. Treatment monitoring is recommended for all patients receiving Pracophora. /US Product Label Includes/
Prograf is indicated for organ rejection prevention in patients who have received allogeneic heart transplants. Prograf is recommended for use in combination with azathioprine or mycophenolate mofetil (MMF) and corticosteroids. /US Product Label Includes/
For more complete data on the therapeutic uses of tacrolimus (13 in total), please visit the HSDB record page.

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Drug Warnings
/Black Box Warning/ Malignancies and Serious Infections. Increased risk of developing lymphoma and other malignancies, especially cutaneous malignancies, due to immunosuppression. Increased susceptibility to bacterial, viral, fungal, and protozoan infections, including opportunistic infections. Prograf should only be prescribed by physicians experienced in immunosuppressive therapy and the management of organ transplant patients. Patients receiving this medication should be treated in a healthcare facility with adequate laboratory and ancillary medical resources. The physician responsible for maintenance therapy should have all information necessary for patient follow-up. /Warning/ Warning: The long-term safety of topical calcineurin inhibitors has not been established. While causality has not been established, rare malignancies (such as skin cancer and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Protopic ointment. Therefore: Prolonged continuous use of topical calcineurin inhibitors, including Protopic ointment, should be avoided in any age group and should be limited to areas of atopic dermatitis; Protopic ointment is not suitable for children under 2 years of age; only 0.03% Protopic ointment is suitable for children aged 2–15 years. For malignant or precancerous skin conditions (such as cutaneous T-cell lymphoma (CTCL)), topical tacrolimus should be avoided because the clinical presentation of these conditions may be similar to dermatitis. Due to the potential increased risk of skin cancer, patients using topical tacrolimus are advised to limit sun or other UV exposure by wearing protective clothing and using a broad-spectrum sunscreen with a high SPF. For more complete (42) drug warnings about tacrolimus, please visit the HSDB record page.

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Pharmacodynamics
Tacrolimus reduces the activity of peptidyl prolyl isomerase by forming a new complex with the immunoaffinity FKBP-12 (FK506-binding protein). Tacrolimus inhibits T-lymphocyte signaling and IL-2 transcription. Tacrolimus has similar activity to cyclosporine but with a lower incidence of rejection. Tacrolimus has also been shown to be effective in the topical treatment of eczema, especially atopic eczema. It suppresses inflammation in a similar way to steroids, but with less potency. A significant advantage of tacrolimus in dermatology is that it can be applied directly to the face; topical steroids cannot be used on the face because they significantly thin the facial skin. In other parts of the body, topical steroids are often a better treatment option. Cyclosporine A and FK506 inhibit T-cell and B-cell activation, as well as other processes crucial for an effective immune response. In T lymphocytes, these drugs interfere with an unknown step in the signaling process from T cell antigen receptors to cytokine genes that coordinate the immune response. The presumed intracellular receptors for FK506 and cyclosporine are cis-trans prolyl isomerases. Drug binding inhibits isomerase activity, but studies of other prolyl isomerase inhibitors and analysis of cyclosporine-resistant mutants in yeast suggest that the drug's effect stems not from the inhibition of isomerase activity, but from the formation of an inhibitory complex between the drug and the isomerase. The transcription factor NF-AT, crucial for early T cell gene activation, appears to be a specific target of cyclosporine A and FK506, as transcription mediated by this protein is blocked in T cells treated with these drugs, with little effect on other transcription factors such as AP-1 and NF-κB. This paper demonstrates that NF-AT is formed when the antigen receptor signals to induce the translocation of a pre-existing cytoplasmic subunit to the nucleus and its binding to a newly synthesized nuclear subunit. FK506 and cyclosporine A can block the translocation of cytoplasmic components without affecting the synthesis of nuclear subunits. [1]

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After T cell receptor (TCR) recognizes an antigen, it initiates a series of events, including the transcription of lymphokine genes, especially the transcription of interleukin-2 (IL-2), which ultimately leads to T cell activation. The immunosuppressants cyclosporine A (CsA) and FK-506 prevent T cell proliferation by inhibiting the Ca(2+)-dependent events required to induce IL-2 transcription. The complex formed by FK-506 or CsA with their respective intracellular binding proteins can inhibit the calmodulin-dependent protein phosphatase calcineurin in vitro. The pharmacological significance of this observation for immunosuppression or drug toxicity is unclear. Although calcineurin is present in lymphocytes, it has not been considered to be involved in TCR-mediated lymphokine gene activation or general transcriptional regulation. This article reports that transfection with the calcineurin catalytic subunit increases the half-maximal inhibitory concentration (IC50) of the immunosuppressants FK-506 and CsA, and that the mutant subunit synergizes with phorbol ester to activate the interleukin-2 promoter in a drug-sensitive manner. These results suggest that calcineurin is an integral part of the T cell receptor (TCR) signaling pathway, as it plays a role in drug-sensitive interleukin-2 promoter activation. [2]

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The immunosuppressants cyclosporine A (CsA) and FK-506 bind to different families of intracellular proteins (immunavidins), referred to as cycloavidin and FK-506-binding protein (FKBP), respectively. Recent in vitro studies have shown that the CsA-cycloavidin complex and the FK 506-FKBP-12 complex can bind to and inhibit the activity of calcineurin, a calcium-dependent serine/threonine phosphatase. We investigated the effects of drug treatment on phosphatase activity in T lymphocytes. Calcineurin is expressed in T cells, and its activity can be measured in cell lysates. Both CsA and FK506 can specifically inhibit the activity of intracellular calcineurin, and their drug concentrations are comparable to those that inhibit the production of interleukin-2 (IL-2) in activated T cells. Although rapamycin can also bind to FKBP, its biological activity is different from that of FK506 and it has no effect on the activity of calcineurin. In addition, excessive rapamycin inhibits the effect of FK506, which may be due to rapamycin displacing FK506 from FKBP. These results indicate that calcineurin is a target of drug-immunoaffin complexes in vivo and establishes the physiological role of calcineurin in T cell activation. [3]

C44H71NO13

822.05

821.492

C, 64.29; H, 8.71; N, 1.70; O, 25.30

109581-93-3

Tacrolimus;104987-11-3

5282315

White to off-white solid powder

871.7ºC at 760 mmHg

127-129°

481ºC

1.73E-35mmHg at 25°C

fungus Streptomyces tsukubaensis.

4.512

4

13

7

58

1480

14

O1[C@]2(C(C(N3C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@]3([H])C(=O)O[C@]([H])(/C(/C([H])([H])[H])=C(\[H])/[C@]3([H])C([H])([H])C([H])([H])[C@]([H])([C@@]([H])(C3([H])[H])OC([H])([H])[H])O[H])[C@]([H])(C([H])([H])[H])[C@]([H])(C([H])([H])C([C@]([H])(C([H])([H])C([H])=C([H])[H])C([H])=C(C([H])([H])[H])C([H])([H])[C@]([H])(C([H])([H])[H])C([H])([H])[C@@]([H])([C@]1([H])[C@]([H])(C([H])([H])[C@@]2([H])C([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])=O)O[H])=O)=O)O[H].O([H])[H] |c:78|

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

(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-prop-2-enyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone;hydrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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