Details of the Drug

General Information of Drug (ID: DM2FGRT)

Drug Name

Clavulanate

Synonyms

Clavulansaeure; Clavulox; Acide clavulanique; Acido clavulanico; Acidum clavulanicum; CLAVULANIC ACID; Clavulansaeure [INN]; Clavulinic Acid; Sodium Clavulanate; Antibiotic MM 14151; MM 14151; Acide clavulanique [INN-French]; Acido clavulanico [INN-Spanish]; Acidum clavulanicum [INN-Latin]; BRL-14151; Clavulanic acid (INN); Clavulanic acid [BAN:INN]; Clavulox (TN); MM-14151; (2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (Z)-(2R,5R)-3-(2-Hydroxyethyliden)-7-oxo-4-oxa-1-azabicyclo(3.2.0)heptan-2-carbonsaeure; (Z)-(2R,5R)-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo(3.2.0)heptane-2-carboxylic acid; 3008-B; 4-Oxa-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3-(2-hydroxyethylidene)-7-oxo-, (2R-(2alpha,3Z,5alpha))

Indication

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[1]
Bacterial infection	1A00-1C4Z	Approved	[2]
Staphylococcal pneumonia	N.A.	Approved	[1]
Staphylococcus aureus infection	N.A.	Approved	[1]
Streptococcal pneumonia	N.A.	Approved	[1]
Urinary tract infection	GC08	Approved	[1]
Pneumonia due to Klebsiella pneumoniae	CA40.03	Investigative	[1]
Sinusitis	CA0A.Z	Investigative	[1]
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Therapeutic Class

Antibiotics

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

199.16

Logarithm of the Partition Coefficient (xlogp)

-1.2

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
Bioavailability: 75% of drug becomes completely available to its intended biological destination(s) [4]
Clearance: The clearance of drug is 0.21 L/min [5]
Elimination: About 40 to 65% of the clavulanic acid is excreted as unchanged drug in urine during the first 6 hours following ingestion [6]
Half-life: The concentration or amount of drug in body reduced by one-half in 45 - 90 minutes [7]
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 31.38107 micromolar/kg/day [8]
Unbound Fraction: The unbound fraction of drug in plasma is 0.91% [9]
Vd: The volume of distribution (Vd) of drug is 12 L [5]

Adverse Drug Reaction (ADR)

ADR Term	Variation	Related DOT	DOT ID	REF
Liver injury	HLA-A*30:02	HLA-A	OTAH14LU	[10]
Liver injury	Not Available	CCR9 GPR28	OT5FSOD8	[11]
Liver injury	Not Available	CCR4 CMKBR4	OT68KZ9B	[11]
Liver injury	Not Available	CXCR3 GPR9	OTIGS220	[11]
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Chemical Identifiers

Formula: C8H9NO5
IUPAC Name: (2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Canonical SMILES: C1[C@@H]2N(C1=O)[C@H](/C(=C/CO)/O2)C(=O)O
InChI: InChI=1S/C8H9NO5/c10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4/h1,6-7,10H,2-3H2,(H,12,13)/b4-1-/t6-,7-/m1/s1
InChIKey: HZZVJAQRINQKSD-PBFISZAISA-N

Cross-matching ID

PubChem CID: 5280980
ChEBI ID: CHEBI:48947
CAS Number: 58001-44-8
DrugBank ID: DB00766
TTD ID: D0X7JN

Combinatorial Drugs (CBD)

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Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Staphylococcus Beta-lactamase (Stap-coc blaZ)	TTHI19T	BLAC_STAAU	Inhibitor	[12]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1)	OTRI4UR1	CP8B1_HUMAN	Gene/Protein Processing	[13]
Alcohol dehydrogenase 1A (ADH1A)	OTTS983E	ADH1A_HUMAN	Gene/Protein Processing	[13]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Gene/Protein Processing	[13]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Gene/Protein Processing	[14]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Gene/Protein Processing	[13]
ATP-binding cassette sub-family G member 5 (ABCG5)	OT1OMY93	ABCG5_HUMAN	Gene/Protein Processing	[13]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Gene/Protein Processing	[13]
C-C chemokine receptor type 4 (CCR4)	OT68KZ9B	CCR4_HUMAN	Drug Response	[11]
C-C chemokine receptor type 9 (CCR9)	OT5FSOD8	CCR9_HUMAN	Drug Response	[11]
C-X-C chemokine receptor type 3 (CXCR3)	OTIGS220	CXCR3_HUMAN	Drug Response	[11]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Clavulanate (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Clavulanate and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[15]
Bedaquiline	DM3906J	Moderate	Increased risk of hepatotoxicity by the combination of Clavulanate and Bedaquiline.	Antimicrobial drug resistance [MG50-MG52]	[16]
Pexidartinib	DMS2J0Z	Major	Increased risk of hepatotoxicity by the combination of Clavulanate and Pexidartinib.	Bone/articular cartilage neoplasm [2F7B]	[17]
Cannabidiol	DM0659E	Moderate	Increased risk of hepatotoxicity by the combination of Clavulanate and Cannabidiol.	Epileptic encephalopathy [8A62]	[18]
Brentuximab vedotin	DMWLC57	Moderate	Increased risk of hepatotoxicity by the combination of Clavulanate and Brentuximab vedotin.	Hodgkin lymphoma [2B30]	[19]
Mipomersen	DMGSRN1	Major	Increased risk of hepatotoxicity by the combination of Clavulanate and Mipomersen.	Hyper-lipoproteinaemia [5C80]	[20]
Teriflunomide	DMQ2FKJ	Major	Increased risk of hepatotoxicity by the combination of Clavulanate and Teriflunomide.	Hyper-lipoproteinaemia [5C80]	[21]
BMS-201038	DMQTAGO	Major	Increased risk of hepatotoxicity by the combination of Clavulanate and BMS-201038.	Hyper-lipoproteinaemia [5C80]	[22]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of Clavulanate and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[23]
Idelalisib	DM602WT	Moderate	Increased risk of hepatotoxicity by the combination of Clavulanate and Idelalisib.	Mature B-cell leukaemia [2A82]	[16]
Leflunomide	DMR8ONJ	Major	Increased risk of hepatotoxicity by the combination of Clavulanate and Leflunomide.	Rheumatoid arthritis [FA20]	[21]
Trabectedin	DMG3Y89	Moderate	Increased risk of hepatotoxicity by the combination of Clavulanate and Trabectedin.	Solid tumour/cancer [2A00-2F9Z]	[18]
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References

1	Clavulanate FDA Label
2	FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 065063.
3	BDDCS applied to over 900 drugs
4	Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
5	Bolton GC, Allen GD, Davies BE, Filer CW, Jeffery DJ: The disposition of clavulanic acid in man. Xenobiotica. 1986 Sep;16(9):853-63. doi: 10.3109/00498258609038967.
6	Public assessment report: CO-AMOXCOO
7	Amoxicillin and potassium clavulanate: an antibiotic combination. Mechanism of action, pharmacokinetics, antimicrobial spectrum, clinical efficacy and adverse effects. Pharmacotherapy. 1984 May-Jun;4(3):122-36.
8	Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
9	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
10	HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity. PLoS One. 2013 Jul 9;8(7):e68111. doi: 10.1371/journal.pone.0068111. Print 2013.
11	ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
12	A sensitive coupled HPLC/electrospray mass spectrometry assay for SPM-1 metallo-beta-lactamase inhibitors. Assay Drug Dev Technol. 2009 Apr;7(2):170-9.
13	Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
14	An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
15	European Medicines Agency "Summary on compassionate use. Remdesivir Gilead.".
16	Product Information. Hivid (zalcitabine). Roche Laboratories, Nutley, NJ.
17	Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
18	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
19	Product Information. Adcetris (brentuximab vedotin). Seattle Genetics Inc, Bothell, WA.
20	Product Information. Kynamro (mipomersen). Genzyme Corporation, Cambridge, MA.
21	Canadian Pharmacists Association.
22	Product Information. Juxtapid (lomitapide). Aegerion Pharmaceuticals Inc, Cambridge, MA.
23	Bodmer M, Sulz M, Stadlmann S, Droll A, Terracciano L, Krahenbuhl S "Fatal liver failure in an adult patient with acute lymphoblastic leukemia following treatment with L-asparaginase." Digestion 74 (2006): epub. [PMID: 16988508]