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Benzathine benzylpenicillin

Benzathine benzylpenicillin (rINN) is a form of penicillin also known as benzathine penicillin. It is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 24 weeks after a single IM dose.

 

Therapeutic use

For use in the treatment of severe infections caused by penicillin G-susceptible microorganisms when rapid and high penicillin levels are required such as in the treatment of septicemia, meningitis, pericarditis, endocarditis and severe pneumonia.

Dosage and Administration

Benzathine penicillin is available in suspension containing 450 mg/ml for IM administration. In addition, vials of a mixture containing benzathine penicillin 450 mg, procaine penicillin 300 mg, and potassium penicillin G 187 mg are available for IM use. Benzathine Pen G, when injected IM in doses of 600,0001,200,000 units (0.450.9 g), maintains a low serum concentration of Pen G for a period of 13 weeks. Single injections of benzathine Pen G have been used for treatment of S. pyogenes infections [1], diphtheria carriers [2], and syphilis [3], whereas monthly injections are used for rheumatic fever prophylaxis. This compound must never be given intravenously.

Toxicology

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
mouse LD50 intraperitoneal 460mg/kg (460mg/kg) BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD

LUNGS, THORAX, OR RESPIRATION: DYSPNEA

BEHAVIORAL: EXCITEMENT
Antibiotics and Chemotherapy Vol. 4, Pg. 633, 1954.
mouse LD50 oral 2gm/kg (2000mg/kg)   Drugs in Japan Vol. 6, Pg. 774, 1982.

 

 

Pharmacokinetic

Benzathine Pen G produces prolonged therapeutic serum levels after IM injection. In young adults, after a single injection of 1.8 g of benzathine Pen G, the mean serum Pen G concentration was 0.2 mg/ml after 48 hours, 0.05 mg/ml at 6 days, and 0.02 mg/ml at 13 days. At 13 days, 33% of subjects already had negligible serum Pen G concentrations, and thereafter no subjects had significant serum levels. After the same dose was given to elderly subjects, mean serum levels of 0.37, 0.1, 0.05 and 0.04 mg/ml occurred at 48 hours, 6 days, 13 days, and 20 days, respectively. Thereafter, serum Pen G levels became undetectable [4]. Prolonged and higher serum levels in elderly subjects are due to delayed renal excretion of Pen G. Administration 0.9 g of benzathine penicillin to young adults was studied [5]. Mean serum Pen G levels remained 0.02 mg/ml for 21 days, but by 28 days only 44% of the serum samples had detectable levels of Pen G. It was concluded that more frequent than 4-weekly IM injections are needed for rheumatic fever chemoprophylaxis.
 

Bioavailability 15-30%
Protein binding 45-68%
Metabolism 16-30% of intramuscular dose is metabolized to penicilloic acid, an inactive metabolite.

Small amounts of 6-aminopenicillanic acid recovered in the urine. A small percentage of the drug appears to be hydroxylated into one or more active metabolites, which are excreted via urine.

Half-life 0.40.9 hours
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd (l/kg) 0.530.67 
Clearance 560ml/min
Excretion Kidneys. Nonrenal clearance includes hepatic metabolism and, to a lesser extent, biliary excretion.

Absorption

Rapidly absorbed following both intramuscular and subcutaneous injection. Initial blood levels following parenteral administration are high but transient. Oral absorption in fasting, healthy humans is only about 15-30% as it is very susceptible to acid-catalyzed hydrolysis.

Distribution


Excretion

Penicillin G is eliminated by the kidneys. Nonrenal clearance includes hepatic metabolism and, to a lesser extent, biliary excretion.

Metabolism

About 16-30% of an intramuscular dose is metabolized to penicilloic acid, an inactive metabolite. Small amounts of 6-aminopenicillanic acid have been recovered in the urine of patients on penicillin G. A small percentage of the drug appears to be hydroxylated into one or more active metabolites, which are also excreted via urine.

Mechanism of Action

By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, penicillin G 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; it is possible that penicillin G interferes with an autolysin inhibitor.

Other pharmacological effects

 


Medicinal Chemistry

CAS number:  1538-09-6   EINECS: 216-260-5

Molecular Formula: C16H20N2.2C16H18N2O4S

Average mass:   909.123596 Da

Monoisotopic mass: 908.360107 Da

 

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

SMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)Cc3ccccc3)C(=O)O)C.CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)Cc3ccccc3)C(=O)O)C.c1ccc(cc1)CNCCNCc2ccccc2

Std. InChI: 1S/2C16H18N2O4S.C16H20N2/c2*1-16(2)12(15(21)22)18-13(20)11(14(18)23-16)17-10(19)8-9-6-4-3-5-7-9;1-3-7-15(8-4-1)13-17-11-12-18-14-16-9-5-2-6-10-16/h2*3-7,11-12,14H,8H2,1-2H3,(H,17,19)(H,21,22);1-10,17-18H,11-14H2/t2*11-,12+,14-;/m11./s1  

ACD/LogP: 1.667 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -1.31 ACD/LogD (pH 7.4): -2.06
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: 6 #H bond donors: 2
#Freely Rotating Bonds: 4 Polar Surface Area: 92.22 2
Index of Refraction:   Molar Refractivity: cm3
Molar Volume: cm3 Polarizability: 10-24cm3
Surface Tension: dyne/cm Density: g/cm3
Flash Point: 355 C Enthalpy of Vaporization: 102.51 kJ/mol
Boiling Point: 663.3 C at 760 mmHg Vapour Pressure: 1.69E-18 mmHg at 25C

 

 

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility:

logP:

pKa:
 

Stability:

 


1. Ginsburg C.M., McCracken Jr G.H., Zweighaft T.C. "Serum penicillin concentrations after intramuscular administration of benzathine penicillin G in children". Pediatrics 69: 452,  (1982).

2. McCloskey R.V., Green M.J., Eller J., Smilack J. "Treatment of diphtheria carriers: benzathine penicillin, erythromycin and clindamycin". Ann. Intern. Med. 81: 788,  (1974).

3. McCracken Jr G.H. "Pharmacological basis for antimicrobial therapy in newborn infants". Am. J. Dis. Child 128: 407,  (1974).

4. Collart P., Poitevin M., Milovanovic A et al. "Kinetic study of serum penicillin concentrations after single doses of benzathine and benethamine penicillins in young and old people". Br. J. Vener. Dis. 56: 355, (1980).

5. Kaplan E.L., Berrios X., Speth J. et al. "Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after intramuscular injection of 1 200 000 units". J. Pediatr. 115: 146, (1989a).

 

 

 

 

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