Details of the Drug

General Information of Drug (ID: DMTBKF3)

• Drug Name: Piperacillin
• Synonyms: PIPC; Peperacillin; Peracin; Pipercillin; Pipracil; Pipril; PIPERACILLIN SODIUM; Piperacillin Monosodium Salt; Piperacillin anhydrous; Cl-227193; Peracin (TN); Piperacillin (INN); Piperacillin (anhydrous); Pipracil, Piper; T-1220; Zobactin (TN); (2S,5R,6R)-6-[[(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (2S,5R,6R)-6-{[(2R)-2-{[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino}-2-phenylacetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (2S-(2alpha,5alpha,6beta(S*)))-6-(((((4-Ethyl-2,3-dioxopiperazin-1-yl)carbonyl)amino)phenylacetyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid; 4-ethyl-2,3-dioxopiperazine carbonyl ampicillin; 6-(D-(-)-alpha-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamido)phenylacetamido)penicillanicacid; 6beta-{(2R)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carboxamido]-2-phenylacetamido}-2,2-dimethylpenam-3alpha-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); 517.6
  Topological Polar Surface Area (xlogp); 0.5
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 8
• ADMET Property:
  Absorption: The drug is not absorbed after oral administration [2]
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 4 mL/min/kg [4]
  Elimination: 71% of drug is excreted from urine in the unchanged form [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 36 - 72 minutes [4]
  Metabolism: The drug is not metabolised [2]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 772.84985 micromolar/kg/day [5]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.5% [4]
  Vd: The volume of distribution (Vd) of drug is 0.101 L/kg [6]
  Water Solubility: The ability of drug to dissolve in water is measured as 714.3 mg/mL [3]
• Chemical Identifiers:
  Formula: C23H27N5O7S
  IUPAC Name: (2S,5R,6R)-6-[[(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
  Canonical SMILES: CCN1CCN(C(=O)C1=O)C(=O)N[C@H](C2=CC=CC=C2)C(=O)N[C@H]3[C@@H]4N(C3=O)[C@H](C(S4)(C)C)C(=O)O
  InChI: InChI=1S/C23H27N5O7S/c1-4-26-10-11-27(19(32)18(26)31)22(35)25-13(12-8-6-5-7-9-12)16(29)24-14-17(30)28-15(21(33)34)23(2,3)36-20(14)28/h5-9,13-15,20H,4,10-11H2,1-3H3,(H,24,29)(H,25,35)(H,33,34)/t13-,14-,15+,20-/m1/s1
  InChIKey: IVBHGBMCVLDMKU-GXNBUGAJSA-N
• Cross-matching ID:
  PubChem CID: 43672
  ChEBI ID: CHEBI:8232
  CAS Number: 61477-96-1
  DrugBank ID: DB00319
  TTD ID: D04ZAH
  VARIDT ID: DR00857
  INTEDE ID: DR2410

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Bacterial Penicillin binding protein (Bact PBP)	TTJP4SM	NOUNIPROTAC	Binder	[7]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[8]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Beta-lactamase (blaB)	DET9I1W	BLAC_BACUN	Substrate	[9]
Beta-lactamase (blaB)	DEYIEO5	AMPC_SERMA	Substrate	[10]
Beta-lactamase (blaB)	DEEZ5CV	BLO1_KLEOX	Substrate	[11]

Drug-Drug Interaction (DDI) Information of This Drug

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Anisindione	DM2C48U	Moderate	Increased risk of bleeding by the combination of Piperacillin and Anisindione.	Coagulation defect [3B10]	[29]
Mycophenolic acid	DMU65NK	Moderate	Altered absorption of Piperacillin due to GI flora changes caused by Mycophenolic acid.	Crohn disease [DD70]	[30]
Probenecid	DMMFWOJ	Minor	Decreased elimination of Piperacillin caused by Probenecid mediated competitive inhibition of renal tubular secretion.	Inborn purine/pyrimidine/nucleotide metabolism error [5C55]	[31]
Methotrexate	DM2TEOL	Major	Decreased elimination of Piperacillin caused by Methotrexate mediated competitive inhibition of renal tubular secretion.	Leukaemia [2A60-2B33]	[32]
Warfarin	DMJYCVW	Moderate	Increased risk of bleeding by the combination of Piperacillin and Warfarin.	Supraventricular tachyarrhythmia [BC81]	[29]
Mycophenolate mofetil	DMPQAGE	Moderate	Altered absorption of Piperacillin due to GI flora changes caused by Mycophenolate mofetil.	Transplant rejection [NE84]	[30]

References

• [1] Zosyn (piperacillin/tazobactam) reformulation: Expanded compatibility and coadministration with lactated Ringer's solutions and selected aminoglycosides. Ther Clin Risk Manag. 2008 Apr;4(2):303-14.
• [2] 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.
• [3] BDDCS applied to over 900 drugs
• [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] An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
• [7] In vitro antienterococcal activity explains associations between exposures to antimicrobial agents and risk of colonization by multiresistant enter... J Infect Dis. 2004 Dec 15;190(12):2162-6.
• [8] 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.
• [9] Purification and characterization of a new beta-lactamase from Bacteroides uniformis. Antimicrob Agents Chemother. 1995 Jul;39(7):1458-61.
• [10] Determination of the antibiotic resistance rates of Serratia marcescens isolates obtained from various clinical specimens. Niger J Clin Pract. 2019 Jan;22(1):125-130.
• [11] Characterization of piperacillin/tazobactam-resistant klebsiella oxytoca recovered from a nosocomial outbreak. PLoS One. 2015 Nov 5;10(11):e0142366.
• [12] Prevalence of antimicrobial resistance genes in Bacteroides spp. and Prevotella spp. Dutch clinical isolates. Clin Microbiol Infect. 2019 Sep;25(9):1156.e9-1156.e13.
• [13] Antibiotic therapy for inducible AmpC beta-lactamase-producing Gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides? Int J Antimicrob Agents. 2012 Oct;40(4):297-305.
• [14] Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Drug Metab Dispos. 2006 Apr;34(4):547-55.
• [15] 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.
• [16] Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR. Res Microbiol. 2017 Jun;168(5):443-449.
• [17] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [18] The intestinal H+/peptide symporter PEPT1: structure-affinity relationships. Eur J Pharm Sci. 2004 Jan;21(1):53-60.
• [19] 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.
• [20] Effects of amino acid alterations in penicillin-binding proteins (PBPs) 1a, 2b, and 2x on PBP affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor in 18 clinical isolates of penicillin-susceptible, -intermediate, and -resistant pneumococci. Antimicrob Agents Chemother. 2002 May;46(5):1273-80.
• [21] Bacteriological characteristics of Staphylococcus aureus isolates from humans and bulk milk. J Dairy Sci. 2008 Feb;91(2):564-9.
• [22] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [23] Activities of antibiotics against methicillin-resistant Staphylococcus aureus with particular reference to synergetic effect between ticarcillin and fosfomycin on penicillinase non-producing methicillin-resistant S. aureus. Jpn J Antibiot. 1993 Jun;46(6):421-7.
• [24] Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
• [25] Penicillin-binding protein sensitive to cephalexin in sporulation of Bacillus cereus. Microbiol Res. 1997 Sep;152(3):227-32.
• [26] Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30.
• [27] Relationship between penicillin-binding protein patterns and beta-lactamases in clinical isolates of Bacteroides fragilis with different susceptibility to beta-lactam antibiotics. J Med Microbiol. 2004 Mar;53(Pt 3):213-21.
• [28] Resistance of Pseudomonas aeruginosa to cefsulodin: modification of penicillin-binding protein 3 and mapping of its chromosomal gene. J Antimicrob Chemother. 1990 Apr;25(4):513-23.
• [29] Alexander DP, Russo ME, Fohrman DE, Rothstein G "Nafcillin-induced platelet dysfunction and bleeding." Antimicrob Agents Chemother 23 (1983): 59-62. [PMID: 6830209]
• [30] Product Information. CellCept (mycophenolate mofetil). Roche Laboratories, Nutley, NJ.
• [31] Allen MB, Fitzpatrick RW, Barratt A, Cole RB "The use of probenecid to increase the serum amoxycillin levels in patients with bronchiectasis." Respir Med 84 (1990): 143-6. [PMID: 2371437]
• [32] Kwon OC, Lee JS, Kim YG, Lee CK, Yoo B, Hong S. Safety of the concomitant use of methotrexate and a prophylactic dose of trimethoprim-sulfamethoxazole.?Clin Rheumatol. 2018;37(12):3215-3220. [PMID: 29383453]