Details of the Drug

General Information of Drug (ID: DMS9503)

• Drug Name: Benzylpenicillin
• Synonyms: penicillin g; Benzylpenicillinic acid; Free penicillin II; Pencillin G; 61-33-6; Benzylpenicillin G; Bencilpenicilina; Benzylpenicillinum; Benzyl penicillin; Free penicillin G; Dropcillin; Pharmacillin; Gelacillin; Liquacillin; Benzopenicillin; Cilopen; Pradupen; Benzylpenicilline; Specilline G; Cilloral; Cosmopen; Ursopen; Galofak; Free benzylpenicillin; Compocillin G; Phenylacetamidopenicillanic acid; 6-(2-Phenylacetamido)penicillanic acid; Pfizerpen; Benzyl-6-aminopenicillinic acid
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 334.4
  Topological Polar Surface Area (xlogp); 1.8
  Rotatable Bond Count (rotbonds); 4
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 5
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [1]
  Clearance: The clearance of drug is 560 mL/min in healthy humans [2]
  Half-life: The concentration or amount of drug in body reduced by one-half in 0.4C0.9 hours [3]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 564.6676 micromolar/kg/day [4]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.4% [3]
  Vd: The volume of distribution (Vd) of drug is 0.53-0.67 L/kg [2]
• Chemical Identifiers:
  Formula: C16H18N2O4S
  IUPAC Name: (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
  Canonical SMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)CC3=CC=CC=C3)C(=O)O)C
  InChI: InChI=1S/C16H18N2O4S/c1-16(2)12(15(21)22)18-13(20)11(14(18)23-16)17-10(19)8-9-6-4-3-5-7-9/h3-7,11-12,14H,8H2,1-2H3,(H,17,19)(H,21,22)/t11-,12+,14-/m1/s1
  InChIKey: JGSARLDLIJGVTE-MBNYWOFBSA-N
• Cross-matching ID:
  PubChem CID: 5904
  ChEBI ID: CHEBI:18208
  CAS Number: 61-33-6
  DrugBank ID: DB01053
  TTD ID: D00QAR
  VARIDT ID: DR00488
  INTEDE ID: DR2164

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Bacterial Penicillin binding protein 1 (Bact pbp)	TTTKCMH	PBPA_ECOLI; PBPB_ECOLI; PBPC_ECOLI	Binder	[5]
Bacterial Penicillin binding protein 3 (Bact mrcA)	TT85JMW	FTSI_ECOLI	Binder	[6]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Organic anion transporting polypeptide 3A1 (SLCO3A1)	DTVNRXW	SO3A1_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 4A1 (SLCO4A1)	DT8H2IC	SO4A1_HUMAN	Substrate	[7]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[10]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[11]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Beta-lactamase (blaB)	DEV0KWQ	Q8KT52_9BACT	Substrate	[12]
N-acylhomoserine lactone acylase (lacA)	DEIU0XN	A0A0A1VBK6_9BURK	Substrate	[13]
Beta-lactamase (blaB)	DET9I1W	BLAC_BACUN	Substrate	[14]
Beta-lactamase (blaB)	DENJ2SQ	BLAB_BACFG	Substrate	[12]
Beta-lactamase (blaB)	DE37FJH	C6JIU1_FUSVA	Substrate	[12]
Beta-lactamase (blaB)	DEAILCM	A0A246EJV2_9BACT	Substrate	[15]
Beta-lactamase (blaB)	DERPJ4F	A0A2S8IKB0_BURCE	Substrate	[16]
Beta-lactamase (blaB)	DESIWFO	Q8GQK7_9FLAO	Substrate	[17]
Beta-lactamase (blaB)	DEQX0DG	Q8RIK5_FUSNN	Substrate	[18]
Beta-lactamase (blaB)	DEBAZ7H	F9DGI4_9BACT	Substrate	[15]
Beta-lactamase (blaB)	DEA5OYT	A0A4U8WDG3_9FLAO	Substrate	[19]

Drug-Drug Interaction (DDI) Information of This Drug

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Anisindione	DM2C48U	Moderate	Increased risk of bleeding by the combination of Benzylpenicillin and Anisindione.	Coagulation defect [3B10]	[75]

References

• [1] BDDCS applied to over 900 drugs
• [2] An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
• [3] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [4] 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
• [5] Overexpression, purification and biochemical characterization of a class A high-molecular-mass penicillin-binding protein (PBP), PBP1* and its soluble derivative from Mycobacterium tuberculosis. Biochem J. 2002 Feb 1;361(Pt 3):635-9.
• [6] 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.
• [7] Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun. 2000 Jun 24;273(1):251-60.
• [8] Drug transport in corneal epithelium and blood-retina barrier: emerging role of transporters in ocular pharmacokinetics. Adv Drug Deliv Rev. 2006 Nov 15;58(11):1136-63.
• [9] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [10] Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Toxicol Sci. 2006 May;91(1):140-9.
• [11] Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos. 2011 Jun;39(6):1031-8.
• [12] Antimicrobial drugs used in the management of anaerobic infections in children. Drugs. 1983 Dec;26(6):520-9.
• [13] A novel quorum-quenching N-acylhomoserine lactone acylase from Acidovorax sp. strain MR-S7 mediates antibiotic resistance. Appl Environ Microbiol. 2017 Jun 16;83(13). pii: e00080-17.
• [14] Purification and characterization of a new beta-lactamase from Bacteroides uniformis. Antimicrob Agents Chemother. 1995 Jul;39(7):1458-61.
• [15] Beta-lactamase production in Prevotella intermedia, Prevotella nigrescens, and Prevotella pallens genotypes and in vitro susceptibilities to selected antimicrobial agents. Antimicrob Agents Chemother. 1999 Oct;43(10):2383-8.
• [16] Characterization of the penA and penR genes of Burkholderia cepacia 249 which encode the chromosomal class A penicillinase and its LysR-type transcriptional regulator. Antimicrob Agents Chemother. 1997 Nov;41(11):2399-405.
• [17] EBR-1, a novel Ambler subclass B1 beta-lactamase from Empedobacter brevis. Antimicrob Agents Chemother. 2002 Oct;46(10):3223-7.
• [18] beta-lactamase production and antimicrobial susceptibility of oral heterogeneous Fusobacterium nucleatum populations in young children. Antimicrob Agents Chemother. 1999 May;43(5):1270-3.
• [19] Genetic and biochemical characterization of CGB-1, an Ambler class B carbapenem-hydrolyzing beta-lactamase from Chryseobacterium gleum. Antimicrob Agents Chemother. 2002 Sep;46(9):2791-6.
• [20] Detection and characterization of beta-lactamase genes in subgingival bacteria from patients with refractory periodontitis. FEMS Microbiol Lett. 2005 Jan 15;242(2):319-24.
• [21] 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.
• [22] Antibacterial activity of cefoperazone against anaerobic bacteria (author's transl). Jpn J Antibiot. 1980 Nov;33(11):1171-82.
• [23] Beta-lactamase production and antimicrobial susceptibility of subgingival bacteria from refractory periodontitis. Oral Microbiol Immunol. 2004 Oct;19(5):303-8.
• [24] Beta-lactamase production and susceptibilities to amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavulanate, cefoxitin, imipenem, and metronidazole of 320 non-Bacteroides fragilis Bacteroides isolates and 129 fusobacteria from 28 U.S. centers. Antimicrob Agents Chemother. 1990 Aug;34(8):1546-50.
• [25] Prevotella strains and lactamic resistance gene distribution in different oral environments of children with pulp necrosis. Int Endod J. 2018 Nov;51(11):1196-1204.
• [26] Preclinical Mouse Models To Study Human OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions in Vivo. Mol Pharm. 2015 Dec 7;12(12):4259-69.
• [27] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [28] Identification of drugs and drug metabolites as substrates of multidrug resistance protein 2 (MRP2) using triple-transfected MDCK-OATP1B1-UGT1A1-MRP2 cells. Br J Pharmacol. 2012 Mar;165(6):1836-1847.
• [29] The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15. Pharmacogenet Genomics. 2008 May;18(5):424-33.
• [30] 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.
• [31] Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta. 2009 Jul;405(1-2):49-52.
• [32] FDA Drug Development and Drug Interactions
• [33] Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Drug Metab Dispos. 2006 Apr;34(4):547-55.
• [34] 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.
• [35] Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR. Res Microbiol. 2017 Jun;168(5):443-449.
• [36] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [37] The intestinal H+/peptide symporter PEPT1: structure-affinity relationships. Eur J Pharm Sci. 2004 Jan;21(1):53-60.
• [38] 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.
• [39] 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.
• [40] Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metab Pharmacokinet. 2004 Oct;19(5):369-74.
• [41] Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther. 2002 Apr;301(1):293-8.
• [42] Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24.
• [43] Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86.
• [44] Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol Cell Physiol. 2005 Nov;289(5):C1075-84.
• [45] Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J Neurochem. 2004 Aug;90(4):931-41.
• [46] Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol. 2005 Oct;57(10):1305-11.
• [47] The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther. 2007 Sep;322(3):1221-7.
• [48] Aspirin and probenecid inhibit organic anion transporter 3-mediated renal uptake of cilostazol and probenecid induces metabolism of cilostazol in the rat. Drug Metab Dispos. 2014 Jun;42(6):996-1007.
• [49] LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001 Jun;120(7):1689-99.
• [50] Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur J Pharmacol. 2008 Apr 14;584(1):57-65.
• [51] 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.
• [52] 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.
• [53] Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705.
• [54] The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res. 2016 Jan 4;44(D1):D372-9. (ID: 2.A.60.1.20)
• [55] Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP. J Pharm Sci. 2017 Sep;106(9):2688-2694.
• [56] Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther. 2004 Feb;308(2):438-45.
• [57] Human platelets express organic anion-transporting peptide 2B1, an uptake transporter for atorvastatin. Drug Metab Dispos. 2009 May;37(5):1129-37.
• [58] pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm. 2011 Aug 1;8(4):1303-13.
• [59] Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos. 2006 Jul;34(7):1229-36.
• [60] Drug Interactions in Infectious Diseases.
• [61] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008 Oct;36(10):2014-23.
• [62] Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1188-97.
• [63] Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3569-74.
• [64] Involvement of estrone-3-sulfate transporters in proliferation of hormone-dependent breast cancer cells. J Pharmacol Exp Ther. 2004 Dec;311(3):1032-7.
• [65] Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001 May;142(5):2005-12.
• [66] 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.
• [67] Clinical relevance of antibiotic-induced endotoxin release in patients undergoing hepatic resection. World J Surg. 1999 Jan;23(1):75-9.
• [68] 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.
• [69] Bactericidal effect of piperacillin alone and combined. Presse Med. 1986 Dec 20;15(46):2297-302.
• [70] Moxalactam (6059-S), a new 1-oxa-beta-lactam: binding affinity for penicillin-binding proteins of Escherichia coli K-12.
• [71] In vitro evaluation of E1040, a new cephalosporin with potent antipseudomonal activity. Antimicrob Agents Chemother. 1988 May;32(5):693-701.
• [72] 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.
• [73] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [74] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [75] Alexander DP, Russo ME, Fohrman DE, Rothstein G "Nafcillin-induced platelet dysfunction and bleeding." Antimicrob Agents Chemother 23 (1983): 59-62. [PMID: 6830209]