Properties of MM 13902 and other carbapenem antibiotics in vitro and in vivo.

Basker, Michael J.; Boon, R. J.; Box, Stephen J.; Prestige, E. A.; Smith, G. M.; Spear, S. R.

doi:10.7164/antibiotics.36.416

Cited by 13 publications

(2 citation statements)

References 12 publications

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“…Stability in kidney homogenates. Kidney homogenates were prepared in MOPS (morpholinepropanesulfonic acid) buffer as described previously (2). Compounds were assayed by reverse-phase high-pressure liquid chromatography as described above.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic studies and renal dehydropeptidase stability of the new beta-lactamase inhibitor BRL 42715 in animals

Coleman

Griffin

Upshon

1991

Antimicrob Agents Chemother

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. Agents Chemother. 33:1580Chemother. 33: -1587Chemother. 33: , 1989. The pharmacokinetics of BRL 42715 were studied following oral and parenteral administration in inice, rats, rabbits, beagle dogs, and cynomolgus monkeys. The elimination half-life (tQ12) of BRL 42715 following intravenous administration was 7 min in rats, 6.2 min in rabbits, 11 min in dogs, and 18 min in cynomolgus monkeys; and interspecies scaling indicated a tj12 of 31 min in humans. Urinary recovery was 24 to 43% in the three species studied. A linear relationship was observed between the dose and the theoretical concentration in blood at time zero and between the dose and area under the concentration-time curve following intravenous administration to mice. Extravascular dosing in mice, rats, and dogs resulted in an increase in t1/2, suggesting a depot effect.BRL 42715 was absorbed in mice following an oral dose (bioavallability of 0.2), but was not absorbed in rats, dogs, or cynomolgus monkeys to any significant extent. The binding of BRL 42715 in serum was 27 to 38% in mouse, rat, and dog sera but was somewhat higher (68 to 70%) in primate and human sera. BRL 42715 was not readily hydrolyzed by the renal dehydropeptidase enzymes of any of the five species studied.BRL 42715 is a penem derivative which is a potent inhibitor of a broad range of ,B-lactamases, including the chromosomally mediated enzymes of Enterobacter, Citrobacter, and Pseudomonas species, against which all other Plactamase inhibitors have poor activity (9). The pharmacokinetics of BRL 42715 were studied in laboratory animals, and these data are reported here.The enzyme renal dehydropeptidase I (RDHP) is known to be a major cause of metabolic inactivation of carbapenems such as imipenem in both laboratory animals and humans. Inhibition of this enzyme by the RDHP inhibitor cilastatin resulted in a six-to eightfold increase in the urinary recovery of imipenem and reduced nephrotoxic potential (12). Certain penem antibiotics are also known to be hydrolyzed by RDHP (11), and it was considered necessary in the early stages of evaluation to determine the stability of BRL 42715 compared with those of the Schering penems SCH 29482 and SCH 34343 and the carbapenems BRL 13902 (3) and imipenem in various kidney homogenates. The results of that study are also reported here. MATERIALS AND METHODSTest compounds. BRL 13902 and BRL 42715 were prepared by SmithKline Beecham Pharmaceuticals. Cilastatin and imipenem were gifts from Merck Sharp & Dohme, Rahway, N.J. SCH 29482 and SCH 34343 were gifts from Schering-Plough Corp., Bloomfield, N.J.Binding of drug to serum. Duplicate samples of BRL 42715 were diluted in pooled fresh serum to a final concentration of 100 ,ug/ml, and the solution was left at room temperature for 15 min, following which samples were centrifuged in an Amicon micropartition system at 1,500 x g for 20 min. BRL 42715 was assayed by high-pressure liquid chromatography using a Waters MicrobondaPak C18 RP column in an RCM-* Corresponding author. 100 unit and was eluted with ...

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetic studies and renal dehydropeptidase stability of the new beta-lactamase inhibitor BRL 42715 in animals

Coleman

Griffin

Upshon

1991

Antimicrob Agents Chemother

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“…The only substance studied in animals and humans is MM 13902 (2). A crude mouse kidney preparation degrades 100 ,ug of this compound per ml at a rate of 1.5 ,g/ml per min, the agent being one-sixteenth as stable as thienamycin.…”

Section: Microbiological Activity Andmentioning

confidence: 99%

In vitro and pharmacokinetic properties of the carbapenems

Wise¹

1986

Antimicrob Agents Chemother

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β‐Lactamase Inhibitors

Stam

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The antibacterial effectiveness of penicillins, cephalosporins, and other β‐lactam antibiotics depends on the inactivation of transpeptidases involved in bacterial cell wall synthesis. Bacteria that are resistant to β‐lactam antibiotics often produce enzymes called β‐lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the β‐lactam ring to give products devoid of antibacterial activity. One approach to combating antibiotic resistance caused by β‐lactamase is to inhibit the enzyme. Effective combinations of enzyme inhibitors with β‐lactam antibiotics such as penicillins or cephalosporins result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. The most important β‐lactamases to inhibit clinically are the gram‐positive penases, the gram‐negative TEM, which are Richmond‐Sykes type III, and the gram‐negative chromosomal cephalosporinases–cephases which are Richmond‐Sykes type I. These enzymes may be referred to as penase, TEM(III), and cephase(I). These clinically important β‐lactamases are serine proteases that form an acyl enzyme intermediate with β‐lactam substrates and β‐lactam‐derived β‐lactamase inhibitors. A number of β‐lactamase‐resistant penicillins and cephalosporins were found to be β‐lactamase inhibitors. No clinically useful inhibitors have been identified from this class. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important β‐lactamases, including penases and Richmond‐Sykes types II, III, IV, V, VI ( Bacteroides ). Carbapenems are another class of natural product β‐lactamase inhibitors. Many penem β‐lactamase inhibitors are potent antibacterials. Penicillanic acid sulfone, (2( S )‐ cis )‐3,3‐dimethyl‐7‐oxo‐4,4‐dioxide‐4‐thia‐1‐azabicyclo [3.2.0]heptane‐2‐carboxylic acid (sulbactam) ( , ), C 8 H 11 NO 5 S, is a weak antibacterial, but is a potent irreversible inactivator of many β‐lactamases, including penases and Richmond‐Sykes type II, III, IV, V, and VI ( Bacteroides ) β‐lactamases. Sulbactam is better than clavulanic acid against type I cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sulfones have been reported to be β‐lactamase inhibitors. Among penam β‐lactamase inhibitors, of 6‐β‐bromopenicillanic acid, a potent inhibitor, has progressed to clinical trials. Although a broad range of β‐lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid manufactured by SmithKline Beecham is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin, C 15 H 16 N 2 O 6 S, has the trade name, Timentin. The oral version of sulbactam in combination with ampicillin, produced by Pfizer is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any β‐lactam antibiotic as Betamaze.

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Properties of MM 13902 and other carbapenem antibiotics in vitro and in vivo.

Cited by 13 publications

References 12 publications

Pharmacokinetic studies and renal dehydropeptidase stability of the new beta-lactamase inhibitor BRL 42715 in animals

Pharmacokinetic studies and renal dehydropeptidase stability of the new beta-lactamase inhibitor BRL 42715 in animals

In vitro and pharmacokinetic properties of the carbapenems

β‐Lactamase Inhibitors

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