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Pheneticillin

With the discovery of the penicillin nucleus, 6-APA, it became possible to synthesize new penicillins by the introduction of side chains [1]. Phenoxyethylpenicillin, an oral penicillin analogous to penicillin V, was the first penicillin produced semisynthetically. Penicillin V and phenethicillin are very similar, but differ slightly in their antibacterial activity and absorption from the gastrointestinal tract. They are both formulated as potassium salts. Penicillin V is the only phenoxypenicillin commonly available.

Therapeutic use

For the treatment of mild to moderately severe infections (e.g. dental infection, infections in the heart, middle ear infections, rheumatic fever, scarlet fever, skin infections, upper and lower respiratory tract infections) due to microorganisms.

Pheneticillin is usually used only for the treatment of mild to moderate infections, and not for severe or deep-seated infections since absorption can be unpredictable. Except for the treatment or prevention of infection with Streptococcus pyogenes (which is uniformly sensitive to penicillin), therapy should be guided by bacteriological studies (including sensitivity tests) and by clinical response. Patients treated initially with parenteral benzylpenicillin may continue oral treatment with pheneticillin once a satisfactory clinical response has been obtained.

For prophylaxis against rheumatic fever, pheneticillin given orally twice a day is used as an alternative to injections of benzathine penicillin given every two weeks.
 

 

Dosage and Administration

 

Toxicology

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
mouse LD50 intracrebral 52250ug/kg (52.25mg/kg)   Journal of Antibiotics, Series B. Vol. 16, Pg. 40, 1963.

 

Pharmacokinetic

The comparative pharmacodynamics and clinical pharmacokinetics of phenoxymethylpenicillin and pheneticillin have been reported [2].

The relative AUC (mg l-1 h) for phenoxymethylpenicillin (PM), acid and potassium salt, and pheneticillin (PE), potassium salt, after oral administration, calculated from published data is reported in the table below:

Author Oral dose PM acid PM K+ salt PE
Berlin & Brante (1959) 150 2.21 3.23 -
Kraushaar & Givannini (1959) 240 2.84 3.02 -
Peck & Griffith (1958) 250 4.21 6.20 -
Spitzy & Doujak (1959) 250 3.50 3.78 -
McCarthy & Finland (1960) 500 - 1.85 2.24
Bond et. al. (1963) 250 - 4.04 5.55
Simon et. al. (1976) 600 - 6.81 5.07
Overbosch  et. al. (1985) 500 9.29 - 29.32


 

Bioavailability 86%
Protein binding 78-80%
Metabolism  
Half-life 56 min
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd 22.5 l
Clearance 295.1  ml/min
Excretion  

Absorption

 

Distribution


Excretion

 

Metabolism

 

Mechanism of Action

By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, penicillin V inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins.

Other pharmacological effects

The inhibitory effect of Phenoxymethylpenicillin on the growth of S. aureus in vitro, is 2.13 times more potent than pheneticillin.

The potency ratio of Phenoxymethylpenicillin to pheneticillin against S. aureus in an experimental mouse-thigh infection is only 1.25 to 1. This is explained by the difference in the AUC after subcutaneous administration of Phenoxymethylpenicillin (0.47mg l-1 h) and pheneticillin (0.92mg l-1 h).


Medicinal Chemistry

CAS number:  147-55-7 EINECS:

Molecular Formula: C17H20N2O5S

Average mass: 364.416107 Da

Monoisotopic mass:  364.109283 Da

Systematic name: (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[(2-phenoxypropanoyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: CC(C(=O)N[C@H]1[C@@H]2N(C1=O)[C@H](C(S2)(C)C)C(=O)O)OC3=CC=CC=C3

Std. InChI: 1S/C17H20N2O5S/c1-9(24-10-7-5-4-6-8-10)13(20)18-11-14(21)19-12(16(22)23)17(2,3)25-15(11)19/h4-9,11-12,15H,1-3H3,(H,18,20)(H,22,23)/t9?,11-,12+,15-/m1/s1

ACD/LogP: 2.220.26 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -0.75 ACD/LogD (pH 7.4): -1.50
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 7 #H bond donors: 2
#Freely Rotating Bonds: 5 Polar Surface Area: 121.24 2
Index of Refraction: 1.638 Molar Refractivity: 92.70.4 cm3
Molar Volume: 258.05.0 cm3 Polarizability: 36.70.5 10-24cm3
Surface Tension: 65.35.0 dyne/cm Density: 1.40.1 g/cm3
Flash Point: 361.331.5 C Enthalpy of Vaporization: 104.03.0 kJ/mol
Boiling Point: 673.955.0 C at 760 mmHg Vapour Pressure: 0.02.2 mmHg at 25C

 

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility:

logP: 2.2

pKa:
 

Stability:

 


1. Batchelor F.R., Doyle F.P., Nayler J.H.C., Rolinson G.N. "Synthesis of penicillin: 6-aminopenicillanic acid in penicillin fermentation". Nature 183: 257, (1959).

2. D. OVERBOSCH, H. MATTIE & R. van FURTH. "Comparative pharmacodynamics and clinical pharmacokinetics of phenoxymethylpenicillin and pheneticillin". Br. J. clin. Pharmac. 19, 657-668, (1985).

 

 

 

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