Comparing the reduction of nitroimidazoles in bacteria and mammalian tissues and relating it to biological activity

Goldman, Peter; Koch, R.; Yeung, Tin-Chuen; Chrystal, Ewan J. T.; Beaulieu, Bernard B.; McLafferty, Martha A.; Sudlow, Gillian

doi:10.1016/0006-2952(86)90553-8

Cited by 60 publications

(8 citation statements)

References 32 publications

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“…In two recent studies performed in healthy volunteers and in patients with chronic renal failure (Paulos et al 1989;Gonzalez-Martin et al 1992), we reported low serum concentrations of nifurtimox after a single oral dose of 15 mg kg-'. Because there was not a parenteral dosage form of nifurtimox, it was not possible to know the absolute systemic availability in man.…”

Section: Discussionsupporting

confidence: 43%

The disposition of nifurtimox in the rat isolated perfused liver: effect of dose size

González-Martín¹,

Ponce²,

Inostroza

et al. 1993

Journal of Pharmacy and Pharmacology

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The disposition of nifurtimox was studied in the rat isolated perfused liver using a recirculating system. The drug was administered as a bolus (5.0, 15.0 or 30.0 micrograms mL-1), and its disappearance was monitored by analysing perfusate samples. In all experiments perfusate disappearance was monoexponential, and no significant difference was found between the three doses for the elimination constant (0.016, 0.011 and 0.012 min-1, respectively), half-life (46.6, 65.8 and 66.8 min, respectively), extraction rate (0.128, 0.091 and 0.099, respectively) and distribution volume (41.1, 47.3 and 30.7 mL g-1, respectively). At 30 micrograms mL-1 the hepatic clearance was lower than the other concentrations of nifurtimox (0.66, 0.51 and 0.34 mL min-1 g-1, respectively). Relatively little parent drug was recovered from the liver at the end of the perfusions. In summary, nifurtimox is cleared slowly from the rat isolated perfused liver, is poorly extracted by hepatocyte cells and is completely metabolized from 2 to 4 h after perfusion.

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Section: Discussionsupporting

confidence: 43%

The disposition of nifurtimox in the rat isolated perfused liver: effect of dose size

González-Martín¹,

Ponce²,

Inostroza

et al. 1993

Journal of Pharmacy and Pharmacology

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“…Post 22758, Egypt (fax π2 45 2960450, e-mail abeerelnahas/ hotmail.com). wards 1986 ;Goldman 1986;Walton & Workman 1987). The prerequisite for this is nitroreductases which are capable of reducing the nitro group in animal organs and tissues (Schmid & Schmid 1999).…”

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confidence: 99%

Reproductive and Cytogenetic Toxicity of Metronidazole in Male Mice

El‐Nahas

El-Ashmawy

2004

Basic Clin Pharma Tox

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The purpose of this study was to examine the effects of metronidazole (500 mg/kg b.wt. daily by gavage for 14 consecutive days) on male fertility, haematopoiesis and genotoxic affinity. Mature male Swiss mice were treated with metronidazole and divided into 3 groups each with 10 animals, examined after 2 weeks, 1 and 2 months from the onset of drug administration. The results demonstrated that metronidazole significantly (PϽ0.05) decreased the weight of the testes, epididymides and accessory sexual organs (seminal vesicles and prostates) after one month from the onset of treatment. While accessory sexual organ weights were restored after 2 months from onset of treatment, the decrease in testes and epididymides weights persisted until 2 months later. The deleterious effects of metronidazole on reproductive organ weights might be due to a decrease in testosterone level after 2 weeks, and 1 and 2 months from the onset of treatment. Metronidazole induced a significant decrease in motile sperm and an increase in abnormal sperm after 1 month. The viability of sperm was normal after 2 months. Metronidazole induced anaemia characterized by decreased erythrocyte and leukocytic counts, haemoglobin content and haematocrit %. The ability of oral metronidazole administration to induce genotoxic damage in somatic cells of mice was evaluated using mitotic index, micronuclei and chromosomal aberration. A significant reduction in mitotic activity was observed two weeks from the onset of drug administration, restoration occured after one month. A significant and persistence increase in the frequency of chromosomal aberration and micronucleus was observed at all periods of the experiment. In conclusion, the results of this study indicate that 1) metronidazole (500 mg/kg by gavage) for 14 days caused a harmful effect on male fertility in mice after one and two months from start of administration, 2) metronidazole induced anaemia after one month from start of administration, 3) metronidazole at this high dose level (3 times the therapeutic dose in mice) has the ability to induce genotoxic effects in somatic cells.

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“…41), and it is most likely these compounds that have the antibacterial effect. The reduction continues, to give final products that have no antibacterial activity and which are released into the culture medium (8,13,15,41). F. nttcleatum reduces and releases the final products of the reduction of metronidazole, such as acetamide, into the culture medium thus permitting the subsequent growth of B. endodontalis.…”

Section: Discussionmentioning

confidence: 99%

The effect of subminimal inhibitory concentrations of antimicrobial agents on three bacterial mixtures

Lacroix

Mayrand

1989

Oral Microbiology and Immunology

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A test tube technique was developed to screen bacterial mixtures to detect interbacterial interactions that play a role in determining sensitivity to antimicrobial agents. We found 3 mixtures where these bacterial interactions change the sensitivity to antimicrobials or change the proportions of each bacterial species in the mixture. The mixtures were: Fusobacterium nucleatum 102.3 and Bacteroides endodontalis ATCC 35406; F. nucleatum 102.3 and B. endodontalis BN11 a-f; and Capnocytophaga ochracea 1956c and Eubacterium saburreum 162.4. The antimicrobials used were metronidazole for the first 2 mixtures and tetracycline for the last. F. nucleatum seems to protect B. endodontalis from the action of metronidazole. Conversely, the growth inhibition of C. ochracea by E. saburreum was lifted when tetracycline was present. We also found that the growth of C. ochracea can then permit the subsequent growth of E. saburreum. The test tube method permits the evaluation both of interbacterial interactions and the detection of any protective mechanism against antimicrobial agents in a bacterial mixture. We found that F. nucleatum 102.3 can decrease the metronidazole level in the culture medium, and by the use of 14C-metronidazole we demonstrated that acetamide is produced from metronidazole.

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Comparing the reduction of nitroimidazoles in bacteria and mammalian tissues and relating it to biological activity

Cited by 60 publications

References 32 publications

The disposition of nifurtimox in the rat isolated perfused liver: effect of dose size

The disposition of nifurtimox in the rat isolated perfused liver: effect of dose size

Reproductive and Cytogenetic Toxicity of Metronidazole in Male Mice

The effect of subminimal inhibitory concentrations of antimicrobial agents on three bacterial mixtures

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