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Drug

D0505 | tacrolimus

Molecular Formula C44H69NO12
Molecular Weight 804
Structure
State solid
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]
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]
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%.
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.
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.
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.
Trade names Prograf, Advagraf, Protopic
Description calcineruin inhibitor; immunosuppressant.

D

L

L04AD02 Tacrolimus


[L04AD] Calcineurin inhibitors


[L04A] IMMUNOSUPPRESSANTS


[L04] IMMUNOSUPPRESSANTS


[L] Antineoplastic and immunomodulating agents

D11AH01 Tacrolimus


[D11AH] Agents for dermatitis, excluding corticosteroids


[D11A] OTHER DERMATOLOGICAL PREPARATIONS


[D11] OTHER DERMATOLOGICAL PREPARATIONS


[D] Dermatological drugs

Toxicity Dose Time Species Model Method Action Positive criterion Reference
UNCOUPLING rat isolated liver mitochondria measurements of mitochondrial respiration; RST inhibition assay, RST uncoupling assay; IC 50ratio of glucose/galactose assay Negative 53
RESPIRATORY CONTROL RATIO (RCR) 1 μM rat isolated kidney mitochondria Oxygen consumption was measured with a Clark‐type electrode decrease 10% 323
RESPIRATORY CONTROL RATIO (RCR) 3.4E−11 M and 2.3E−8 M rat isolated kidney mitochondria Oxygen consumption was measured with a Clark‐type electrode decrease EC50 ; maximal inhibitory effect was about 20% 323
BASAL RESPIRATION 50 µg/ml 12hr INS-1 cells XF24 Extracellular Flux Analyzer decrease 322
MAXIMAL RESPIRATION 50 µg/ml 12hr INS-1 cells XF24 Extracellular Flux Analyzer decrease 322
PROTON LEAK 50 µg/ml 12hr INS-1 cells XF24 Extracellular Flux Analyzer decrease 322
NON-MITOCHONDRIAL RESPIRATION 50 µg/ml 12hr INS-1 cells XF24 Extracellular Flux Analyzer decrease 322
P/O RATIO ( ADP/O) 1 μM rat isolated kidney mitochondria Oxygen consumption was measured with a Clark‐type electrode decrease 323
ELECTRON TRANSPORT CHAIN rat isolated kidney mitochondria decrease 68
ELECTRON TRANSPORT CHAIN rat isolated liver mitochondria measurements of mitochondrial respiration; RST inhibition assay, RST uncoupling assay; IC 50ratio of glucose/galactose assay Negative 53
TRANSPORT OF CALCIUM 1 μM rat isolated kidney mitochondria Ca2+ fluxes: A specific Ca2+ electrode (Orion 9320) fitted to a Hansatech recorder via a 720A Orion ionometer was used to record Ca2+ movements in extramitochondrial medium in a thermostat‐controlled reaction chamber. Negative 323
SWELLING 1 μM rat isolated kidney mitochondria Measurement of swelling of energized mitochondria: measuring the decrease of optical density at 520 nm, with a Hitachi spectrophotometer (U3000) Negative 323
VOLUME beta cells from isolated rat islets Transmission electron microscopy and 3D reconstruction of mitochondria decrease 322
ROS PRODUCTION 50 µg/ml 12hr INS-1 cells MitoSOX Red staining to detect mitochondrial superoxide anion (O2−) levels by flow cytometric analysis and e time-lapse images of cells treated for 12 h with MitoSOX Red. induce 322
CYTOCHROME C RELEASE 1 μM rat isolated kidney mitochondria The amount of cytochrome c was measured using a Quantikine® M Rat/Mouse Cytochrome c immunoassay after addition of drugs in energized mitochondrial (3 min) or after Ca2+‐induced mitochondrial swelling (3 min). Negative 323

Target Dose Time Species Model Method Action Positive criterion Reference
Quinol--cytochrome-c reductase 1 μM rat isolated kidney mitochondria Mitochondrial complex III assay (ubiquinol‐cytochrome c oxidoreductase) inhibit 30% 323

Pictogram Signal Statements Precautionary Statement Codes
Danger

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.


H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]


H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]


H372 (100%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]


 P201, P202, P260, P264, P270, P281, P301+P310, P308+P313, P314, P321, P330, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)
Danger

Aggregated GHS information provided by 203 companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.


H301 (99.01%): Toxic if swallowed [Danger Acute toxicity, oral]


H361 (97.54%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]


H372 (97.04%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]


Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.


 P201, P202, P260, P264, P270, P281, P301+P310, P308+P313, P314, P321, P330, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)
Danger

H301: Toxic if swallowed [Danger Acute toxicity, oral]


 P264, P270, P301+P310, P321, P330, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)


  • (-)-FK 506 (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-5,19-dihydroxy-3-{(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl}-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(prop-2-en-1-yl)-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-3H-15,19-epoxypyrido[2,1-c][1,4]oxazacyclotricosine-1,7,20,21(4H,23H)-tetrone (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-5,19-dihydroxy-3-{(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-8-prop-2-en-1-yl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-3H-15,19-epoxypyrido[2,1-c][1,4]oxazacyclotricosine-1,7,20,21(4H,23H)-tetrone
    (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-Hexadecahydro-5,19-dihydroxy-3-[(1E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propen-1-yl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)tetrone (E)-(1R,9S,12S,13R,14R,21S,23S,24R,25S,27R)-17-Allyl-1,14-dihydroxy-12-[(E)-2-((3R,4R)-4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0*4,9*]octacos-18-ene-2,3,10,16-tetraone 104987-11-3
    15,19-Epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-, (3S-(3R*(E(1S*,3S*,4S*)),4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*))- 15,19-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(1E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyc 15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(23H)-tetrone,
    4,5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-heptadecahydro-5,19-dihydroxy-3- 581T933 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN
    AB0012538 AB01209746-01 AB01209746_03
    ABP000474 AC-1182 AKOS005145901
    AM81227 AT-2441 Advagraf
    Anhydrous Tacrolimus Astagraf XL Avagraf
    BDBM50030448 BDBM50079777 BRD-K35452788-001-02-1
    BRD-K69608737-001-03-7 BRD-K69608737-001-10-2 BSPBio_001279
    C01375 C44H69NO12 CAS-104987-11-3
    CCRIS 7124 CHEBI:61049 CHEBI:93221
    CHEMBL269732 CHEMBL66247 CS-1507
    D08556 DB00864 DSSTox_CID_26354
    DSSTox_GSID_46354 DSSTox_RID_81557 DTXSID5046354
    EN300-221601 EX-A1677 Envarsus
    Envarsus XR FK 506 FK-506 (Tacrolimus)
    FK-506/Tacrolimus FK506 FR-900506
    FR900506 FT-0082660 Fk-506
    Fujimycin Fujimycin|||FK-506|||FR-900506 GTPL6784
    Graceptor HMS1792O21 HMS1990O21
    HMS2093M19 HMS3403O21 HMS503O21
    HSDB 8195 HY-13756 Hecoria
    IDI1_001040 K506 L 679934
    L-679934 LCP-Tacro LMPK04000003
    M2258 MFCD11045918 Modigraf
    NCGC00163470-01 NCGC00163470-02 NCGC00163470-03
    NCGC00163470-04 NCGC00163470-05 NCGC00163470-06
    NCGC00163470-07 NSC-758659 NSC758659
    Pharmakon1600-01503968 Prograf Prograf (TN)
    Prograft Protopic Protopy
    PubChem18875 Q-201775 Q411648
    QJJXYPPXXYFBGM-LFZNUXCKSA-N SBI-0052894.P002 SC-13591
    SCHEMBL3088 SR-05000001879 SR-05000001879-1
    SR-05000001879-2 SR-05000001879-5 TACROLIMUS MONOHYDRATE
    Tacrolimus (INN) Tacrolimus (anhydrous) Tacrolimus [USAN:INN]
    Tacrolimus [USAN] Tacrolimus anhydrous Tacrolimus solution, 1.0 mg/mL in acetonitrile, ampule of 1 mL, certified reference material;
    Tacrolimus, anhydrous Talymus Tox21_112056
    Tsukubaenolide UNII-Y5L2157C4J W-1246
    Y5L2157C4J ZINC169289411 [(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-14,16-
    dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-,(3S,4R,5S,8R,12S,14S,15R,16S,18R,19R,26aS)- lohexyl]-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propen-1-yl)-, (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)- s5003
    tacrolimus tacrolimus (fk506)

    DrugBank Name tacrolimus
    DrugBank DB00864
    CAS Number 104987-11-3, 109581-93-3
    PubChem Compound 445643
    KEGG Compound ID C01375
    KEGG Drug D00107
    ChEBI 61049
    PharmGKB PA451578