Activity of the cefotaxime (HR756) desacetyl metabolite compared with those of cefotaxime and other cephalosporins

Wise, R.; Wills, P.J.; Andrews, J. M.; Bedford, K. A.

doi:10.1128/aac.17.1.84

Cited by 87 publications

(28 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Incomplete urinary recoveries of cephalosporins such as cephalothin and cefotaxime have been ascribed to enzymatic (hepatic) cleavage of their acetylated side chains. In both instances, desacetyl metabolites with reduced antimicrobial activity and an intact beta-lactam are recovered in the urine of laboratory animals and in humans (6,7,9,20).…”

mentioning

confidence: 99%

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Kropp

Sundelof

Hajdu

et al. 1982

Antimicrob Agents Chemother

318

143

View full text Add to dashboard Cite

Thienamycin (THM), the N-formimidoyl thienamycin derivative MK0787, and related carbapenem antibiotics were metabolized extensively in mice, rats, rabbits, dogs, rhesus monkeys, and chimpanzees. Urinary recovery of THM ranged from a low of 5% in dogs to 58% in rhesus monkeys. Renal clearance rates in dogs and chimpanzees were unusually low, less than glomerular filtration rates. The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance. Degradation was detected only in kidney homogenates. The enzyme activity was membrane bound and sensitive to inhibitors of Zn-metalloenzymes such as EDTA. A renal dipeptidase, dehydropeptidase-I (DHP-I), EC 3.4.13.11, was found to be responsible for the metabolism of the THM-class antibiotics, which exhibit a structural homology to dehydropeptides. A parallel increase in specific activity against THM and the substrate of DHP-I, glycyldehydrophenylalanine, was observed during solubilization and purification of the enzyme from porcine and human renal cortex. DHP-I was found to catalyze the hydrolysis of the beta-lactam ring in THM and MK0787. The products of the enzyme reaction were identical by high-powered liquid chromatography to their respective metabolites found in the urine. Nonbasic Nacylated THM and natural N-acylated carbapenems (epithienamycins and olivanic acids) were degraded 4-to 50-fold faster than THM when exposed to the enzymatic hydrolysis of DHP-I. Good correlations were obtained between the increased susceptibility of the carbapenem antibiotics to DHP-I as measured in the in vitro enzyme assay and the generally lower recoveries of active antibiotic in the urine of test animals. Despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK0787 and its efficacy against experimental systemic infections in animals remain satisfactory.Thienamycin (THM) and the N-formimidoyl thienamycin derivative MK0787 are members of a new class of structurally novel beta-lactam antibiotics, the carbapenems. Both are known for their high orders of activity against a broad spectrum of bacteria (11,18,19). Their breadth of activity is in part attributable to resistance to attack by bacterial beta-lactamases (17).The low recovery of unaltered THM and MK0787 in the urine of laboratory animals suggested that these antibiotics are extensively metabolized. Incomplete urinary recoveries of cephalosporins such as cephalothin and cefotaxime have been ascribed to enzymatic (hepatic) cleavage of their acetylated side chains. In both instances, desacetyl metabolites with reduced antimicrobial activity and an intact beta-lactam are recovered in the urine of laboratory animals and in humans (6,7,9,20).Biochemical studies presented in this report show that low urinary recoveries of THM and MK0787 result from the hydrolysis of the betalactam ring by the renal dipeptidase, dehydropeptidase-I

show abstract

mentioning

confidence: 99%

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Kropp

Sundelof

Hajdu

et al. 1982

Antimicrob Agents Chemother

318

143

View full text Add to dashboard Cite

show abstract

“…Agents Chemother. 1980, 210) and deacetylation of cefotaxime (23). Reversible filament formation was the primary defect observed with cefotaxime.…”

Section: Discussionmentioning

confidence: 95%

“…This has clinical implications regarding the site of infection, the inhibitory levels for bacteria, and the patient's defense status. N:f-Thienamycin is metabolized by dehydropeptidases in the basement membrane of proximal tubules; only 10-15% remains unmetabolized (H. Kropp Although cefotaxime is metabolized to a somewhat lesser extent than N:Jthienamycin (60-70% remains unaltered) (23), the change affects its use against all infections, not just those confined to the urinary tract. The deacetylated form of cefotaxime has only one-tenth the activity of the parent compound, and may pose a therapeutic problem when treating infections with strains that have MIC's ::::> 10 /kg/ml.…”

Section: Discussionmentioning

confidence: 99%

Comparative Activity of N‐Formimidoyl Thienamycin with Third Generation Cephalosporins and Ureido Penicillins against Multiple Resistant Serratia marcescens

Miller

LeFrock

Vercler

1981

Microbiology and Immunology

View full text Add to dashboard Cite

Twenty multiple resistant clinical isolates were tested with N-formimidoyl thienamycin, moxalactam, cefotaxime, cefoperazone, and the three ureidopenicillins: azlocillin, mezlocillin, and piperacillin. A concentration of < 0.97 Itg/ml inhibited 100% of organisms for N:f-thienamycin and cefotaxime, 90% for moxalactam, and 60% for cefoperazone. An increase in inoculum from 10 3 to 10 6 cells reduced activity fourfold for 95% of isolates with cefoperazone, 70% with N-formimidoyl thienamycin, 65% for cefotaxime, but only 15% for moxalactam. For ureidopenicillins, 85% of strains tested had MIC's-c;, 15.6 Itg/m!. An inoculum effect was observed in only 35-50%. At 10 3 , the cidal concentration was the same or twofold greater than the inhibitory level for N:f-thienamycin and cephalosporins in 70% of strains tested and 65% for penicillins. With 10 6 , the 70% value remained for N:f-thienamycin but was reduced to 45% for cefotaxime and 25% for moxalactam; 85% demonstrated>eightfold differences with cefoperazone. Single step high-level resistance was observed to moxalactam (20%). Carbenicillin resistant strains were cross-resistant to the ureidopenicillins. N-fthienamycin and cefotaxime appeared comparable, although important differences between morphological alteration and metabolism may influence their therapeutic effectiveness.

show abstract

“…An approximate serum half-life of 1.1-1.3 h after injection was confirmed in different studies (10)(11)(12)(13). The drug is primarily eliminated by the kidney, but also converted into the less active metabolite desacetyl-cefotaxime in the liver to a significant level (14)(15). Considering the obvious drawbacks of drug administration by injection and potential side effects of high oral dosages, enhancing the oral bioavailability of CEF is a significant model study.…”

Section: Introductionmentioning

confidence: 84%

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

et al. 2017

View full text Add to dashboard Cite

-PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75-30 mM) by rotary film evaporation followed by nanosize reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts. Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nanosized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold.

show abstract

Activity of the cefotaxime (HR756) desacetyl metabolite compared with those of cefotaxime and other cephalosporins

Cited by 87 publications

References 4 publications

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase-I

Comparative Activity of N‐Formimidoyl Thienamycin with Third Generation Cephalosporins and Ureido Penicillins against Multiple Resistant Serratia marcescens

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

Contact Info

Product

Resources

About