Penamecillin is  an acetoxymethyl ester prodrug of benzylpenicillin [1].

Therapeutic use


Dosage and Administration



Acute Toxicity

A suspension of penamecillin in 0.5% carboxymethyl cellulose was administered orally to groups (5 males and 5 females) of mice and rats. No animal died over a 14-day period after a single dose of 5 g/kg body weight.

Chronic administration

Rats. Groups of 20 rats (10 males and 10 females) were given the drug in the diet at a concentration of 0.4%, 0.8%, or 1.6% for a period of 6 1/2 to 7 weeks. A control group received diet alone. At the highest dose the calculated drug intake, on the basis of body weight and food uptake during the 3rd week of the test, was 1.5-1.6 g/kg/day in both males and females. Food intake and growth was not adversely affected apart from a temporary depression in weight gain of females on the highest dose during the first week. The only statistically significant drug-related change occurred in the pituitaries of females which had received the highest dose. These were significantly smaller than in the controls (P<0.05) both on an absolute and relative basis. Histopathological examination of all tissues revealed no evidence of organic injury which could be related to drug treatment.

Dogs. Groups of 4 dogs (2 male and 2 female) were given the drug orally in capsules at 400, 800 or 1,600 mg/kg/day for 51 weeks. A control group was given starch in  capsules. All animals survived and the only untoward effect, observed in 3 of the dogs on the highest dose, was vomiting during the first 3 or 4 days of treatment. In dogs on the highest dose level, alkaline phosphatase and glumatic-oxalo-acetic transminase values were higher than in controls but the differences were not considered to be of biological importance. In the same animals the serum cholesterol values were lower than in the controls.

Histopathological examination of all tissues revealed only one change attributable to drug action, in one dog on the highest dose which showed moderate hydropic vacuolisation within liver cells.


A study of the absorption and excretion of penamecillin, after oral administration in mammals has been performed [2]. It is rapidly hydrolysed by both lipase and preparations of intestinal mucosa. No significant absorption takes place via the lymphatic system. Chloroform extracts of blood, liver and kidney were prepared from six male albino rats which had received 400 mg/kg penamecillin orally as an aqueous suspension. Two hrs after dosing no penamecillin was detected in the tissues.

Penamecillin was readily hydrolysed by serum from the rat, rabbit and dog. In rat serum diluted with 4 volumes of 0.9% NaCl there was very rapid hydrolysis of the compound at room temperature (21C). No penamecillin was detected even at 0, 15 and 30 min, indicating that very rapid breakdown had taken place. Eighty to one hundred per cent of the added activity was recovered as benzylpenicillin.  At pH 3.0 no breakdown was observed during 30 min and good recoveries were obtained. The recovery of penamecillin from the non-enzyme controls showed that no significant breakdown had taken place during the 30-min incubation period. The esterases of rabbit and dog serum were less active than those of the rat. In these species undiluted serum required 20-30 min complete hydrolysis. Preliminary tests using human serum esterases showed a pattern of breakdown similar to that obtained with dog and rabbit serum. Similar experiments using homogenates of intestinal mucosa, gastric mucosa, liver and kidney showed that penamecillin was hydrolysed by the non-specific esterases from these organs. Ten per cent liver homogenates in 0.9% NaCl gave complete hydrolysis at O min, kidney homogenates were
less active, taking 15 min for complete hydrolysis.








Mechanism of Action


Other pharmacological effects


Medicinal Chemistry

CAS number:  983-85-7   EINECS:  213-571-8

Molecular Formula: C19H22N2O6S

Average mass:   406.452789 Da

Monoisotopic mass: 406.119843 Da

Systematic name: (acetyloxy)methyl (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

SMILES:  CC(=O)OCOC(=O)[C@H]1C(S[C@H]2N1C(=O)[C@H]2NC(=O)Cc3ccccc3)(C)C

Std. InChI: 1S/C19H22N2O6S/c1-11(22)26-10-27-18(25)15-19(2,3)28-17-14(16(24)21(15)17)20-13(23)9-12-7-5-4-6-8-12/h4-8,14-15,17H,9-10H2,1-3H3,(H,20,23)/t14-,15+,17-/m1/s1

ACD/LogP: 1.040.88 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): 1.04 ACD/LogD (pH 7.4): 1.04
ACD/BCF (pH 5.5): 3.66 ACD/BCF (pH 7.4): 3.66
ACD/KOC (pH 5.5): 88.11 ACD/KOC (pH 7.4): 88.11
#H bond acceptors: 8 #H bond donors: 1
#Freely Rotating Bonds: 8 Polar Surface Area: 127.31 2
Index of Refraction: 1.609 Molar Refractivity: 102.30.4 cm3
Molar Volume: 295.35.0 cm3 Polarizability: 40.60.5 10-24cm3
Surface Tension: 60.65.0 dyne/cm Density: 1.40.1 g/cm3
Flash Point: 346.231.5 C Enthalpy of Vaporization: 95.63.0 kJ/mol
Boiling Point: 648.855.0 C at 760 mmHg Vapour Pressure: 0.01.9 mmHg at 25C


Major Impurities:


Melting point: 107C

Optical rotation:




1. JANSEN, A. B. A. & RUSSELL, T. J. "Some novel penicillin derivatives". J. Chem. Soc. 2127-2132, (1965).




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