Details of the Drug

General Information of Drug (ID: DM42W1B)

• Drug Name: Cefmetazole
• Synonyms: CMZ; Cefmetazolo; Cefmetazolum; Cefmetazole Monosodium Salt; CS 1170; SKF 83088; U 72791; CS-1170; Cefmetazole [USAN:INN]; Cefmetazolo [INN-Spanish]; Cefmetazolum [INN-Latin]; U-72791A; Cefmetazole (USP/INN); (6R,7S)-7-(2-((Cyanomethyl)thio)acetamido)-7-methoxy-3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid; (6R,7S)-7-(2-((Cyanomethyl)thio)acetamido)-7-methoxy-3-(((1-methyl-1H-tetrazol-5-yl)thiomethyl)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, sodium salt; (6R,7S)-7-({[(cyanomethyl)sulfanyl]acetyl}amino)-7-methoxy-3-{[(1-methyl-1H-tetrazol-5-yl)sulfanyl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; (6R,7S)-7-({[(cyanomethyl)thio]acetyl}amino)-7-(methyloxy)-3-{[(1-methyl-1H-tetrazol-5-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; (6R,7S)-7-[[2-(cyanomethylsulfanyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 6beta-{[(cyanomethyl)sulfanyl]acetamido}-6alpha-methoxy-3-{[(1-methyl-1H-tetrazol-5-yl)sulfanyl]methyl}ceph-3-em-4-carboxylic acid

Indication

Disease Entry	ICD 11	Status	REF
Bacterial infection	1A00-1C4Z	Approved	[1]

• Therapeutic Class: Antibiotics
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 471.5
  Topological Polar Surface Area (xlogp); -0.6
  Rotatable Bond Count (rotbonds); 9
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 12
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [2]
  Bioavailability: The bioavailability of drug is 100% [3]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 1.5 mL/min/kg [4]
  Elimination: 80% of drug is excreted from urine in the unchanged form [2]
  Half-life: The concentration or amount of drug in body reduced by one-half in 1.50 +/- 0.14 hours [4]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 212.0717 micromolar/kg/day [5]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.15% [4]
  Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.13 L/kg [4]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.0942 mg/mL [2]
• Chemical Identifiers:
  Formula: C15H17N7O5S3
  IUPAC Name: (6R,7S)-7-[[2-(cyanomethylsulfanyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
  Canonical SMILES: CN1C(=NN=N1)SCC2=C(N3[C@@H]([C@@](C3=O)(NC(=O)CSCC#N)OC)SC2)C(=O)O
  InChI: InChI=1S/C15H17N7O5S3/c1-21-14(18-19-20-21)30-6-8-5-29-13-15(27-2,17-9(23)7-28-4-3-16)12(26)22(13)10(8)11(24)25/h13H,4-7H2,1-2H3,(H,17,23)(H,24,25)/t13-,15+/m1/s1
  InChIKey: SNBUBQHDYVFSQF-HIFRSBDPSA-N
• Cross-matching ID:
  PubChem CID: 42008
  ChEBI ID: CHEBI:3489
  CAS Number: 56796-20-4
  DrugBank ID: DB00274
  TTD ID: D05UBX
  VARIDT ID: DR00539

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Bacterial Penicillin binding protein 3 (Bact mrcA)	TT85JMW	FTSI_ECOLI	Binder	[6]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[8]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Cefmetazole

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Kanamycin	DM2DMPO	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Kanamycin.	Bacterial infection [1A00-1C4Z]	[32]
Amikacin	DM5PDRB	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Amikacin.	Bacterial infection [1A00-1C4Z]	[32]
Streptomycin	DME1LQN	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Streptomycin.	Bacterial infection [1A00-1C4Z]	[32]
Gentamicin	DMKINJO	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Gentamicin.	Bacterial infection [1A00-1C4Z]	[32]
Tobramycin	DMUI0CH	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Tobramycin.	Bacterial infection [1A00-1C4Z]	[32]

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Framycetin	DMF8DNE	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Framycetin.	Alcoholic liver disease [DB94]	[32]
Mycophenolic acid	DMU65NK	Moderate	Altered absorption of Cefmetazole due to GI flora changes caused by Mycophenolic acid.	Crohn disease [DD70]	[33]
Ethanol	DMDRQZU	Moderate	Decreased metabolism of Cefmetazole caused by Ethanol mediated inhibition of non-CYP450 enzyme.	Cystitis [GC00]	[34]
Ethacrynic acid	DM60QMR	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Ethacrynic acid.	Essential hypertension [BA00]	[35]
Furosemide	DMMQ8ZG	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Furosemide.	Heart failure [BD10-BD1Z]	[35]
Bumetanide	DMRV7H0	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Bumetanide.	Heart failure [BD10-BD1Z]	[35]
Probenecid	DMMFWOJ	Moderate	Decreased elimination of Cefmetazole caused by Probenecid mediated competitive inhibition of renal tubular secretion.	Inborn purine/pyrimidine/nucleotide metabolism error [5C55]	[36]
Mycophenolate mofetil	DMPQAGE	Moderate	Altered absorption of Cefmetazole due to GI flora changes caused by Mycophenolate mofetil.	Transplant rejection [NE84]	[33]
Plazomicin	DMKMBES	Moderate	Increased risk of nephrotoxicity by the combination of Cefmetazole and Plazomicin.	Urinary tract infection [GC08]	[37]

References

• [1] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 050637.
• [2] BDDCS applied to over 900 drugs
• [3] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [4] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [5] 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
• [6] Clinical relevance of antibiotic-induced endotoxin release in patients undergoing hepatic resection. World J Surg. 1999 Jan;23(1):75-9.
• [7] Intestinal transport of beta-lactam antibiotics: analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayers and the transepithelial flux. Pharm Res. 1999 Jan;16(1):55-61.
• [8] Screening of antibiotics that interact with organic anion-transporting polypeptides 1B1 and 1B3 using fluorescent probes. Biol Pharm Bull. 2011;34(3):389-95.
• [9] Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Drug Metab Dispos. 2006 Apr;34(4):547-55.
• [10] Peptide transporter substrate identification during permeability screening in drug discovery: comparison of transfected MDCK-hPepT1 cells to Caco-2 cells. Arch Pharm Res. 2007 Apr;30(4):507-18.
• [11] Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR. Res Microbiol. 2017 Jun;168(5):443-449.
• [12] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [13] The intestinal H+/peptide symporter PEPT1: structure-affinity relationships. Eur J Pharm Sci. 2004 Jan;21(1):53-60.
• [14] Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of the mammalian H+/peptide cotransporter PEPT1. J Med Chem. 2005 Jun 30;48(13):4410-9.
• [15] LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99.
• [16] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [17] Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur J Pharmacol. 2008 Apr 14;584(1):57-65.
• [18] Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metab Dispos. 2011 Jun;39(6):1047-53.
• [19] Relevance of conserved lysine and arginine residues in transmembrane helices for the transport activity of organic anion transporting polypeptide 1B3. Br J Pharmacol. 2010 Feb 1;159(3):698-708.
• [20] Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007 Dec;63(12):1161-9.
• [21] FDA Drug Development and Drug Interactions
• [22] Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705.
• [23] Penicillin-binding protein PBP2 of Escherichia coli localizes preferentially in the lateral wall and at mid-cell in comparison with the old cell pole. Mol Microbiol. 2003 Jan;47(2):539-47.
• [24] Genetic analyses of beta-lactamase negative ampicillin-resistant strains of Haemophilus influenzae isolated in Okinawa, Japan. Jpn J Infect Dis. 2006 Feb;59(1):36-41.
• [25] Bactericidal effect of piperacillin alone and combined. Presse Med. 1986 Dec 20;15(46):2297-302.
• [26] Moxalactam (6059-S), a new 1-oxa-beta-lactam: binding affinity for penicillin-binding proteins of Escherichia coli K-12.
• [27] In vitro evaluation of E1040, a new cephalosporin with potent antipseudomonal activity. Antimicrob Agents Chemother. 1988 May;32(5):693-701.
• [28] Association of amino acid substitutions in penicillin-binding protein 3 with beta-lactam resistance in beta-lactamase-negative ampicillin-resistant Haemophilus influenzae. Antimicrob Agents Chemother. 2001 Jun;45(6):1693-9.
• [29] Mode of Action of the Monobactam LYS228 and Mechanisms Decreasing In Vitro Susceptibility in Escherichia coli and Klebsiella pneumoniae. Antimicrob Agents Chemother. 2018 Sep 24;62(10):e01200-18.
• [30] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [31] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [32] Agencia Espaola de Medicamentos y Productos Sanitarios Healthcare "Centro de informacion online de medicamentos de la AEMPS - CIMA.".
• [33] Product Information. CellCept (mycophenolate mofetil). Roche Laboratories, Nutley, NJ.
• [34] Brown KR, Guglielmo BJ, Pons VG, Jacobs RA "Theophylline elixir, moxalactam, and a disulfiram reaction." Ann Intern Med 97 (1982): 621-2. [PMID: 6214982]
• [35] Chrysos G, Gargalianos P, Lelekis M, Stefanou J, Kosmidis J "Pharmacokinetic interactions of ceftazidime and frusemide." J Chemother 7 Suppl (1995): 107-10. [PMID: 8904125]
• [36] Brown G, Zemcov SJ, Clarke AM "Effect of probenecid on cefazolin serum concentrations." J Antimicrob Chemother 31 (1993): 1009-11. [PMID: 8360120]
• [37] Engle JE, Drago J, Carlin B, Schoolwerth AC "Letter: Reversible acute renal failure after cephalothin." Ann Intern Med 83 (1975): 232-3. [PMID: 1147461]