Drug

D0043 | Doxorubicin

Molecular Formula C27H29NO11
Molecular Weight 543.5
Structure
State solid
Clearance * 324-809 mL/min/m2 [by metabolism and biliary excretion] * 1088 mL/min/m2 [Men] * 433 mL/min/m2 [Women] * 1540 mL/min/m2 [children greater than 2 years of age receiving administration of 10 to 75 mg/m2 doses] * 813 mL/min/m2 [infants younger than 2 years of age receiving administration of 10 to 75 mg/m2 doses]
Volume of distribution The distributive half-life is 5 minutes, which suggests that doxorubicin is rapidly taken up by tissue. Steady state volume of distribution = 809 to 1214 L/m2
Route of elimination 40% of the dose appears in bile in 5 days. 5-12% of the drug and its metabolites appears in urine during the same time period. <3% of the dose recovered in urine was doxorubicinol.
Protein binding Doxorubicin and its major metabolite, doxorubicinol, is 74-76% bound to plasma protein. The extent to binding is independent of plasma concentration up to 1.1 mcg/mL. Doxorubicin does not cross the blood brain barrier.
Half life Terminal half life = 20 - 48 hours.
Trade names Adriamycin, Caelyx, Myoce
Description cytotoxic anthracycline antibiotics; chemotherapy agent; Anticancer

L

L01DB01 Doxorubicin


[L01DB] Anthracyclines and related substances


[L01D] CYTOTOXIC ANTIBIOTICS AND RELATED SUBSTANCES


[L01] ANTINEOPLASTIC AGENTS


[L] Antineoplastic and immunomodulating agents


Toxicity Dose Time Species Model Method Action Positive criterion Reference
MEMBRANE POTENTIAL 8.9 µM 30 mins mouse liver mitochondria Rh123 fluorescence (excitation 485 nm, emission 535 nm) are recorded using a fluorescence multi-well plate reader (mCICCP (20 µM) treatments was considered as the 100% baseline for ΔΨm loss) decrease EC20 36
REDOX CYCLING 278
RESPIRATION 15.9 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. decrease EC20 36
RESPIRATION ND 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Oligomycin A (1µM) was used as 100% baseline for complex II inhibition. Negative EC20 36
ELECTRON TRANSPORT CHAIN decrease 36
GLUCOSE GALACTOSE IC50 RATIO 0.5 LUHMES (Lund human mesencephalic) cells Glc–Gal–NeuriTox assay Negative EC25(NA) [Glc/Gal] 326
IRON HOMEOSTASIS 197
SWELLING 85 µM 30 mins mouse liver mitochondria swelling assay: Absorbance at 545 nm using a fluorescence multi-well plate reader (CaCl2 (50 µM) was considered as the 100% baseline for the swelling ) increase EC20 36
MITOCHONDRIAL DYNAMICS 7.2 μM DXR for 24 hrs Human fibroblasts 247
OXIDATIVE STRESS 250
ROS PRODUCTION increase 197

Target Dose Time Species Model Method Action Positive criterion Reference
NADH:ubiquinone reductase 15.9 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. inhibit EC20 36
Succinate dehydrogenase ND 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Oligomycin A (1µM) was used as 100% baseline for complex II inhibition. Negative EC20 36
Glycerol-3-phosphate dehydrogenase, mitochondrial inhibitor 162
Cytochrome c 23.3 µM 30 mins mouse liver mitochondria Cytochrome c release was evaluated using ELISA kit ( 20 µg/ml Alamethicin was used as 100% baseline) release EC20 36

Pictogram Signal Statements Precautionary Statement Codes
Danger

Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.


H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]


H350 (100%): May cause cancer [Danger Carcinogenicity]


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, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)

Organism Test type Route Dose (normalized dose) Effect Source
rat LD50 intraperitoneal 16mg/kg (16mg/kg) Oyo Yakuri. Pharmacometrics. Vol. 6, Pg. 1075, 1972.
man LDLo unreported 243ug/kg (0.243mg/kg) Postgraduate Medical Journal. Vol. 68, Pg. 69, 1992.
mouse LD50 intraperitoneal 10700ug/kg (10.7mg/kg) Huaxi Yike Daxue Xuebao. Journal of West China University of Medical Sciences. Vol. 20, Pg. 303, 1989.
human LDLo intravenous 400ug/kg (0.4mg/kg) Cancer Chemotherapy Reports, Part 3. Vol. 3, Pg. 33, 1972.
hamster LD10 parenteral 3500ug/kg (3.5mg/kg) Journal of Surgical Oncology. Vol. 15, Pg. 355, 1980.
mouse LD50 unreported 21900ug/kg (21.9mg/kg) Biochemical Pharmacology. Vol. 38, Pg. 167, 1989.
mouse LD50 intravenous 10mg/kg (10mg/kg) Journal of Antibiotics. Vol. 45, Pg. 1373, 1992.
human TDLo intravenous 380mg/kg/31W (380mg/kg) Cancer Vol. 34, Pg. 518, 1974.
rabbit LDLo intrapleural 400ug/kg (0.4mg/kg) Pharmacology and Toxicology Vol. 62, Pg. 84, 1988.
rat LD50 unreported 7mg/kg (7mg/kg) Antibiotiki i Khimioterapiya. Antibiotics and Chemotherapy. Vol. 34, Pg. 216, 1989.
rat LD50 intravenous 10510ug/kg (10.51mg/kg) Toxicology and Applied Pharmacology. Vol. 79, Pg. 412, 1985.
mammal (species unspecified) LD50 intraperitoneal 8500ug/kg (8.5mg/kg) Antibiotiki. Vol. 29, Pg. 748, 1984.
rabbit LD50 intravenous 5mg/kg (5mg/kg) Yiyao Gongye. Pharmaceutical Industry. Vol. 17, Pg. 72, 1986.
human TDLo intravenous 15mg/kg/D (15mg/kg) Cancer Vol. 34, Pg. 518, 1974.
mouse LD50 oral 570mg/kg (570mg/kg) Antibiotiki. Vol. 28, Pg. 298, 1983.
dog LD50 intravenous 2400ug/kg (2.4mg/kg) Drug and Chemical Toxicology. Vol. 6, Pg. 21, 1983.
mouse LDLo intratracheal 2400ug/kg (2.4mg/kg) Toxicology Letters. Vol. 30, Pg. 63, 1986.

  • Acquired immunodeficiency syndrome

  • Acute lymphocytic leukaemia

  • Acute myeloid leukaemia

  • Adenocarcinoma gastric

  • Autoimmune disorder

  • Bladder cancer stage IV

  • Bladder neoplasm

  • Bladder transitional cell carcinoma

  • Bladder transitional cell carcinoma metastatic

  • Bone sarcoma

  • Brain neoplasm

  • Breast cancer stage IV

  • Bronchial carcinoma

  • Cardiac disorder

  • Cardiotoxicity

  • Drug interaction

  • Endometrial cancer

  • Ewing's sarcoma

  • Gastric cancer

  • Hepatic cancer

  • Hepatic cancer metastatic

  • Hepatic function abnormal

  • Hepatocellular carcinoma

  • Hodgkin's disease

  • Hodgkin's disease lymphocyte depletion type stage unspecified

  • Hodgkin's disease lymphocyte predominance type stage unspecified

  • Hypersensitivity

  • Immunodeficiency

  • Kaposi's sarcoma

  • Kaposi's sarcoma AIDS related

  • Leukaemia

  • Lung neoplasm malignant

  • Lymphoma

  • Malaise

  • Malignant melanoma

  • Menopause

  • Metastases to liver

  • Metastasis

  • Metastatic neoplasm

  • Nephroblastoma

  • Neuroblastoma

  • Non-small cell lung cancer

  • Osteosarcoma

  • Ovarian epithelial cancer

  • Ovarian epithelial cancer stage IV

  • Pancreatic carcinoma

  • Plasma cell myeloma

  • Plasmacytoma

  • Renal cancer

  • Rhabdomyosarcoma

  • Sarcoma

  • Small cell lung cancer

  • Squamous cell carcinoma

  • Testis cancer

  • Thymoma

  • Thyroid cancer

  • Breast disorder (0.01)

  • Somnolence (0.051)

  • Abdominal pain

  • Alopecia

  • Amenorrhoea

  • Anaemia

  • Asthenia

  • Back pain

  • Body temperature increased

  • Candida infection

  • Chills

  • Conjunctivitis

  • Constipation

  • Cough

  • Decreased appetite

  • Dermatitis

  • Diarrhoea

  • Discomfort

  • Dizziness

  • Dry skin

  • Dysaesthesia

  • Dyspepsia

  • Dyspnoea

  • Fatigue

  • Febrile neutropenia

  • Feeling abnormal

  • Flushing

  • Gastrointestinal pain

  • Headache

  • Herpes simplex

  • Herpes zoster

  • Hot flush

  • Hypochromic anaemia

  • Ill-defined disorder

  • Infection

  • Keratitis

  • Laboratory test abnormal

  • Lethargy

  • Leukaemia

  • Leukopenia

  • Malaise

  • Menopausal symptoms

  • Mucosal inflammation

  • Mucous membrane disorder

  • Nausea

  • Neuralgia

  • Neuritis

  • Neuropathy peripheral

  • Neutropenia

  • Oral candidiasis

  • Pain

  • Paraesthesia

  • Pharyngitis

  • Phlebitis

  • Rash

  • Sepsis

  • Shock

  • Stomatitis

  • Thrombocytopenia

  • Vomiting

  • Weight decreased

  • (1S,3S)-3,5,12-trihydroxy-3-(hydroxyacetyl)-10-(methyloxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside (1S,3S)-3,5,12-trihydroxy-3-(hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside (1S,3S)-3-Glycoloyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl-(3-amino-2,3,6-tridesoxy-alpha-L-lyxo-hexopyranosid)
    (1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside (1s,3s)-3,5,12-Trihydroxy-3-(hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-l-lyxo-hexopyranoside (7S,9R)-7-[(2S,4S,5S,6S)-4-Amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
    (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-9-glycoloyl-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-quinone;hydrochloride (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride
    (7S,9S)-7-[(2R,4S,5S,6S)-4-azanyl-6-methyl-5-oxidanyl-oxan-2-yl]oxy-4-methoxy-6,9,11-tris(oxidanyl)-9-(2-oxidanylethanoyl)-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride (7S,9S)-7-[[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-2-oxanyl]oxy]-6,9,11-trihydroxy-9-(2-hydroxy-1-oxoethyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride (8S,10S)-10-(((2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracen
    (8S,10S)-10-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione (8S,10S)-10-((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yloxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione (8S,10S)-10-((3-Amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione
    (8S,10S)-10-{[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione (8S-cis)-10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione (8S-cis)-10-(3-Amino-2,3,6-Tr ideoxy-alpha-L-Lyxo-Hexopyranosyl)Oxy-7,8,9,10-Tetrahydro-6,8,11-Trihydroxy-8-(Hydroxyacetyl)-1-Methoxy-5,12-Naphthacenedione
    (8S-cis)-10-(3-Amino-2,3,6-Trideoxy-alpha-L-Lyxo-Hexopyranosyl)Oxy-7,8,9,10-Tetrahydro-6,8,11-Trihydroxy-8-(Hydroxyacetyl)-1-Methoxy-5,12-Naphthacenedione (8S-cis)-10-[(3-Amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexopyranosyl]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione 1,2,3,4,6,11-Hexahydro-4beta,5,12-trihydroxy-4-(hydroxyacetyl)-10-methoxy-6,11-dioxonaphthacen-1beta-yl-3-amino-2,3,6-trideoxy-alpha-L-lyxohexopyranoside
    10-((3-Amino-2,3,6-trideoxy-D-lyxohexopyranosyl)oxy)-8-glycolcyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione 10-((3-Amino-2,3,6-trideoxy-alpha-L-lyso-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione 10336-EP2270008A1
    10336-EP2270014A1 10336-EP2270018A1 10336-EP2270505A1
    10336-EP2272827A1 10336-EP2272832A1 10336-EP2275420A1
    10336-EP2277565A2 10336-EP2277566A2 10336-EP2277567A1
    10336-EP2277568A2 10336-EP2277569A2 10336-EP2277570A2
    10336-EP2277865A1 10336-EP2277876A1 10336-EP2280012A2
    10336-EP2281815A1 10336-EP2289892A1 10336-EP2292280A1
    10336-EP2292614A1 10336-EP2292615A1 10336-EP2292617A1
    10336-EP2295055A2 10336-EP2295416A2 10336-EP2295426A1
    10336-EP2295427A1 10336-EP2298748A2 10336-EP2298764A1
    10336-EP2298765A1 10336-EP2298768A1 10336-EP2298778A1
    10336-EP2298780A1 10336-EP2301536A1 10336-EP2301538A1
    10336-EP2301928A1 10336-EP2301933A1 10336-EP2302382A2
    10336-EP2302383A2 10336-EP2305243A1 10336-EP2305250A1
    10336-EP2305640A2 10336-EP2305642A2 10336-EP2305671A1
    10336-EP2305679A1 10336-EP2305689A1 10336-EP2308562A2
    10336-EP2308812A2 10336-EP2308833A2 10336-EP2308855A1
    10336-EP2308861A1 10336-EP2311453A1 10336-EP2311455A1
    10336-EP2311808A1 10336-EP2311825A1 10336-EP2311827A1
    10336-EP2311829A1 10336-EP2311840A1 10336-EP2311842A2
    10336-EP2316452A1 10336-EP2316832A1 10336-EP2316833A1
    10336-EP2316834A1 10336-EP2371811A2 10336-EP2374454A1
    13171-EP2269989A1 13171-EP2269994A1 13171-EP2270008A1
    13171-EP2270018A1 13171-EP2270505A1 13171-EP2275102A1
    13171-EP2277865A1 13171-EP2277876A1 13171-EP2281815A1
    13171-EP2286812A1 13171-EP2289892A1 13171-EP2292227A2
    13171-EP2292233A2 13171-EP2292614A1 13171-EP2292615A1
    13171-EP2292617A1 13171-EP2295407A1 13171-EP2295412A1
    13171-EP2295413A1 13171-EP2295416A2 13171-EP2298305A1
    13171-EP2298736A1 13171-EP2298746A1 13171-EP2298748A2
    13171-EP2298768A1 13171-EP2298772A1 13171-EP2298780A1
    13171-EP2301933A1 13171-EP2305640A2 13171-EP2305642A2
    13171-EP2305671A1 13171-EP2305679A1 13171-EP2305689A1
    13171-EP2308833A2 13171-EP2308839A1 13171-EP2308861A1
    13171-EP2311827A1 13171-EP2316832A1 13171-EP2316833A1
    13171-EP2316834A1 13171-EP2316937A1 14-Hydroxydaunomycin
    14-Hydroxydaunorubicine 14D928 23214-92-8
    45970-EP2275413A1 45970-EP2287156A1 45970-EP2311807A1
    5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S,10S)- 5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-cis)- 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-, (8S,10S)-
    80168379AG A14403 AB1009243
    ADM ADR AKOS015951330
    AOJJSUZBOXZQNB-TZSSRYMLSA-N Adriablastin Adriacin (hydrochloride salt)
    Adriamycin Adriamycin Adriamycin PFS (hydrochloride salt)
    Adriamycin RDF (hydrochloride salt) Adriamycin semiquinone Adriblas tina
    Adriblastina Adriblastina (TN) Adriblastina (hydrochloride salt)
    Aerosolized Doxorubicin BDBM22984 BDBM32022
    BP-23114 BPBio1_000502 BRD-K92093830-003-04-3
    BRD-K92093830-003-25-8 BSPBio_000456 BSPBio_001031
    C-23275 C01661 CC-23807
    CCRIS 739 CHEBI:28748 CHEMBL53463
    CS-2759 Caelyx (liposomal doxorubicin) Conjugate of doxorubicin with humanized monoclonal antibody LL1 against CD74
    Conjugate of doxorubicin with monoclonal antibody P4/D10 against GP120 D03899 DB00997
    DOX DOX-SL DTXSID8021480
    Doxil Doxorubicin Doxorubicin (USAN/INN)
    Doxorubicin [USAN:INN:BAN] Doxorubicin hydrochloride (hydrochloride salt) Doxorubicin-P4/D10
    Doxorubicin-P4/D10 conjugate Doxorubicin-hLL1 Doxorubicin-hLL1 conjugate
    Doxorubicina Doxorubicina [INN-Spanish] Doxorubicine
    Doxorubicine [INN-French] Doxorubicinum Doxorubicinum [INN-Latin]
    EINECS 245-495-6 FI 106 FT-0601614
    Farmablastina (hydrochloride salt) GR-319 GTPL7069
    HMS2089H06 HSDB 3070 HY-15142A
    Hydroxydaunomycin hydrochlor ide (hydrochloride salt) Hydroxydaunomycin hydrochloride (hydrochloride salt) Hydroxydaunorubicin
    Hydroxydaunorubicin hydrochloride (hydrochloride salt) LMPK13050001 LS-165655
    MCULE-4188577717 MLS000028393 NCGC00024415-35
    NCGC00024415-37 NCGC00024415-38 NCGC00024415-40
    NCGC00024415-41 NCGC00024415-42 NCI-C01514
    NDC 38242-874 Prestwick0_000438 Prestwick1_000438
    Prestwick2_000438 Prestwick3_000438 Probes1_000151
    Probes2_000129 Q18936 Rubex (hydrochloride salt)
    SB21799 SCHEMBL3243 SMP1_000106
    SPBio_002395 TLC D-99 ThermoDox
    UNII-80168379AG ZINC3918087 adiblastine (hydrochloride salt)
    adr iablatina (hydrochloride salt) adriablastine (hydrochloride salt) adriablatina (hydrochloride salt)
    adriblatina (hydrochloride salt) cid_443939 doxorubicin

    DrugBank Name Doxorubicin
    DrugBank DB00997
    CAS Number 111266-55-8, 23214-92-8, 25316-40-9
    PubChem Compound 31703
    KEGG Compound ID C01661
    KEGG Drug D03899
    PubChem.Substance 46507641
    ChEBI 28748
    PharmGKB PA449412
    ChemSpider 29400
    BindingDB 22984.0
    TTD DNC000163
    Wikipedia Doxorubicin
    HET DM2
    DPD 2298

    1. Meyer et al. (2017)
    2. Dykens et al. (2007)
    3. Chan et al. (2005)
    4. Vuda et al. (2016)
    5. Palmeira et al. 1997
    6. Ashley and Poulton (2009)