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Carindacillin (Carbenicillin indanyl)

Carindacillin is a prodrug of carbenicillin [1],  administered orally, as the sodium salt.
 

Therapeutic use


Caridacillin is mainly indicated for therapy of P. aeruginosa urinary tract infections. It may be useful occasionally for the treatment of similar infections caused by Enterobacter spp., P. vulgaris, P. rettgeri, or M. morganii [2-3]. Infections by these pathogens usually occur in patients with some underlying urinary tract pathology, and bacteriuria is often recurrent and difficult to eradicate. Furthermore, superinfection with carbenicillin-resistant organisms such as Klebsiella spp. may occur [4]. Nevertheless, these oral carbenicillins have been used with some success as short-term therapy [3], as a 6-week course of therapy in patients with chronic pyelonephritis [5], or as long-term suppressives in patients with chronic bacteriuria [6].
 

 

Dosage and Administration

The adult dosage is 0.5 or 1 g orally every 6 hours. The same doses can be used to treat certain urinary tract infections in patients with mild to moderate degrees of renal failure. The drug is unsuitable for patients with severe renal failure (creatinine clearance <14 ml/min) because very low carbenicillin concentrations are attained in the urine [8]. Carindacillin therapy is not recommended for children.

Toxicology

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
dog LD50 oral > 500mg/kg (500mg/kg)   Chemotherapy Vol. 17, Pg. 334, 1972.
mouse LD50 oral 3600mg/kg (3600mg/kg)   Chemotherapy Vol. 17, Pg. 334, 1972.
rat LD50 oral 2gm/kg (2000mg/kg)   Chemotherapy Vol. 17, Pg. 334, 1972.

This drug tastes very bitter and, although the tablets have a special coating, many patients complain of an unpleasant after-taste and
nausea. It can also cause diarrhea, especially if the dosage of 1 g 6-hourly is exceeded [9].

Pharmacokinetic

Bioavailability  
Protein binding  
Metabolism  
Half-life  
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd  
Clearance  
Excretion  

Absorption

Carindacillin is acid stable and is well absorbed when administered orally. After absorption, it is rapidly hydrolyzed to carbenicillin plus indanol, probably either in the intestinal mucosa or in the liver [10]. Following an oral dose of 0.5 g of carindacillin to adults, a peak serum level of about 10 mg/ml carbenicillin is reached in 1.01.5 hours. Thereafter, the serum level falls and usually reaches zero at 6 hours. Doubling the dose to 1 g raises the peak serum level to only 1517 mg/ml. Simultaneous administration of probenecid results in higher serum levels, but they are still inadequate for treatment of systemic P. aeruginosa infections. With dosages larger than 1 g 6-hourly, higher serum levels can be obtained, but not in a dose proportional mode. In patients treated with doses greater than 4 g/day, diarrhea is common because a large proportion of the dose is unabsorbed [9].

Distribution


Excretion

In the first 3 hours after an oral dose of 1 g of carindacillin, urine carbenicillin concentrations exceed 1000 mg/ml [9]. All the indanol which is formed when carindacillin is hydrolyzed in vivo is eliminated in the urine as glucuronide and sulfate conjugates [9].

Metabolism

 

Mechanism of Action

 

Other pharmacological effects

 


 

Medicinal Chemistry

CAS number:  26605-69-6  EINECS:

Molecular Formula:  C26H26N2O6S

Average mass: 494.559387 Da

Monoisotopic mass:  494.151154 Da

Systematic name: (2S,5R,6R)-6-([3-(2,3-dihydro-1H-inden-5-yloxy)-3-oxo-2-phenylpropanoyl]amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)C(C3=CC=CC=C3)C(=O)OC4=CC5=C(CCC5)C=C4)C(=O)O)C

Std. InChI: 1S/C26H26N2O6S/c1-26(2)20(24(31)32)28-22(30)19(23(28)35-26)27-21(29)18(15-7-4-3-5-8-15)25(33)34-17-12-11-14-9-6-10-16(14)13-17/h3-5,7-8,11-13,18-20,23H,6,9-10H2,1-2H3,(H,27,29)(H,31,32)/t18?,19-,20+,23-/m1/s1

ACD/LogP: 3.930.33 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): 0.98 ACD/LogD (pH 7.4): 0.20
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 3.66 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 8 #H bond donors: 2
#Freely Rotating Bonds: 7 Polar Surface Area: 138.31 2
Index of Refraction: 1.68 Molar Refractivity: 129.40.4 cm3
Molar Volume: 342.25.0 cm3 Polarizability: 51.30.5 10-24cm3
Surface Tension: 72.85.0 dyne/cm Density: 1.40.1 g/cm3
Flash Point: 445.234.3 C Enthalpy of Vaporization: 123.83.0 kJ/mol
Boiling Point: 812.565.0 C at 760 mmHg Vapour Pressure: 0.03.1 mmHg at 25C

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility: 0.468 mg/L

logP: 3.77

pKa:
 

Stability:

 


1. English A.R., Retsema J.A., Ray V.A., Lynch J.E. "Carbenicillin indanyl sodium, an orally active derivative of carbenicillin". Antimicrob. Agents Chemother. 1 (3): 18591, (1972).

2. Turck M. "The treatment of urinary-tract infections with an oral carbenicillin". J. Infect. Dis. 127 (Suppl): 133, (1973).

3. Leigh D.A., Simmons K. "The treatment of simple and complicated urinary tract infections with carfecillin, a new oral ester of carbenicillin". J. Antimicrob. Chemother. 2: 293, (1976).

4. Hodges G.R., Perkins R.L. "Carbenicillin indanyl sodium oral therapy of urinary tract infections". Arch. Intern. Med. 131: 679, (1973).

5. Michiels H.G.F., Debruyne F.M.J., Moonen W.A. "The treatment of chronic pyelonephritis with carindacillin". Curr. Med. Res. Opin. 5: 394, (1978).

6. Holloway W.J., Taylor W.A. "Long term oral carbenicillin therapy in complicated urinary tract infections". J. Infect. Dis. 127 (Suppl): 143, (1973).

7. Turck M. "The treatment of urinary-tract infections with an oral carbenicillin". J. Infect. Dis. 127 (Suppl): 133, (1973).

8. Cox C.E. "Pharmacology of carbenicillin indanyl sodium in renal insufficiency". J. Infect. Dis. 127 (Suppl): 157, (1973).

9. Knirsch A.K., Hobbs D.C., Korst J.J. "Pharmacokinetics, toleration, and safety of indanyl carbenicillin in man". J. Infect. Dis. 127 (Suppl): 105, (1973).

10. Butler K., English A.R., Ray V.A., Timreck A.E. "Carbenicillin: chemistry and mode of action". J. Infect. Dis. 122 (Suppl): 1, (1970).

 

 

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