The metabolism of 4-aminobiphenyl in rat. I. Reaction of<i>N</i>-hydroxy-4-aminobiphenyl with rat blood<i>in vivo</i>

Karreth, S.; Lenk, Werner

doi:10.3109/00498259109039481

Cited by 10 publications

(1 citation statement)

References 17 publications

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“…This relation could be explained in part by an acetylation-deacetylation imbalance of this drug. This disequilibrium has been described in the metabolism of numerous chemical compounds, such as acrylamides (26,27), 4-aminobiphenyl (25), and sulfadimethoxine (38).…”

Section: Discussionmentioning

confidence: 99%

Possible implications of doxycycline-rifampin interaction for treatment of brucellosis

Colmenero

Fernandez-Gallardo

Agúndez

et al. 1994

Antimicrob Agents Chemother

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We studied the possible interaction between rifampin and doxycycline in 20 patients with brucellosis treated randomly with either doxycycline and streptomycin or doxycycline and rifampin. The doxycycline levels in the plasma of patients in the group treated with rifampin were significantly lower than those in the plasma of patients treated with doxycycline and streptomycin. Furthermore, clearance in patients treated with rifampin was significantly higher than that in patients treated with doxycycline and streptomycin, and consequently, the elimination half-life and the area under the concentration-time curve were significantly lower. There was no therapeutic failure or relapse in the group treated with doxycycline and streptomycin, whereas 2 of 10 patients in the group treated with doxycycline and rifampin had a therapeutic failure or relapse. The plasma doxycycline levels had an inverse correlation with plasma rifampin levels. In the group treated with rifampin, those who were rapid acetylators had lower levels of doxycycline. In conclusion, combined treatment with rifampin reduces the levels of doxycycline in plasma. These data suggest that therapeutic failures or relapses may result from this interaction.Brucellosis is still a serious public health problem in many parts of the world (43). Although the mortality rate as a result of this infection is low (12), it causes frequent complications, particularly those affecting the locomotor system, and these complications sometimes cause serious functional sequelae (3, 15).The organisms of the genus Brucella are known to have a high degree of "in vitro" susceptibility to a number of antimicrobial agents (11,36). However, their location, which is predominantly intracellular, protects them from the actions of many antibiotics. This explains to a great extent the tendency of this organism to cause illness with a long evolution and frequent relapses (41).For several decades the treatment of choice for brucellosis was based on the association of tetracyclines and streptomycin (13,29). Several studies carried out in the beginning of the 1980s showed that rifampin had excellent antibrucellar activity. This fact, together with its good intracellular penetration and ease of administration, made it a drug of great interest for the treatment of brucellosis (7,16,33).Studies with animal models and humans showed that rifampin monotherapy for brucellosis resulted in a high number of therapeutic failures and relapses (20,28). However, when it was used in combination with doxycycline there was a clear synergism and a good therapeutic efficacy (6).In 1986, the Expert Committee on Brucellosis of the Food and Agriculture Organization-World Health Organization recommended the combination of doxycycline-rifampin as the treatment of choice for human brucellosis (24). Later studies showed that the combination doxycycline-rifampin was less effective in practice than the classical treatment of tetracycline and streptomycin (1,14).

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Section: Discussionmentioning

confidence: 99%

Possible implications of doxycycline-rifampin interaction for treatment of brucellosis

Colmenero

Fernandez-Gallardo

Agúndez

et al. 1994

Antimicrob Agents Chemother

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Reactions of Nitrosoarenes with SH Groups

Eyer

Gallemann

2009

Patai's Chemistry of Functional Groups

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Use of a metabolic inhibitor to reduce dapsone‐dependent haematological toxicity

Coleman

Tingle

1992

Drug Development Research

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Coleman, M.D., and M.D. Tingle: Use of a metabolic inhibitor to reduce dapsone-dependent haematological toxicity. Drug Dev. Res. 25:l-16, 1992.Aside from its established use as an antileprotic and anti-inflammatory drug, dapsone is also effective in the therapy of Pneurnocystis carinii pneumonia. Unfortunately, its use is often limited by its dose-dependent toxicity, such as methaemoglobinaemia and haemolysis; the latter condition occurs most frequently in gIucose-6-dehydrogenase deficient individuals. It is also responsible for occasional life-threatening disorders such as agranulocytosis. Dapsone may undergo acetylation, but its toxicity is due to the product of its oxidative metabolism, dapsone hydroxylamine. This is generated in man by the constitutive hepatic cytochrome P450 enzyme IIIA4. Studies in the rat revealed that dapsone-dependent methaemoglobinaemia could be greatly diminished by the co-administration of metabolic inhibitors. In the isolated perfused rat liver, dapsone hydroxylamine levels and hence methaemoglobin formation fell significantly in the presence of cimetidine. In addition, the clearance of the parent drug was retarded, and perfusate concentrations of monoacetyl dapsone increased. The protective effect of cimetidine also reduced methaemoglobin formation in the whole rat during the chronic administration of dapsone. Incubation of dapsone in a two-compartment in vitro system using human tissues in the presence of cimetidine or ketoconazole resulted in a decrease in methaemoglobin formation in all the human livers tested. Although cimetidine was only effective if incubated with microsomes and NADPH prior to the addition of dapsone. Administration of cimetidine (3 x 400 mg daily) to volunteers 3 days prior to and 4 days post administration of a single dose of 100 mg dapsone caused drug concentrations to increase by almost 30%. There was a marked fall in peak methaemoglobin levels and the percentage of the dose excreted in urine as dapsone hydroxylamine N-glucuronide was reduced by almost one third. During high dose dapsone therapy it may be possible that the co-administration of cimetidine might reduce toxicity while maintaining drug efficacy.

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The metabolism of 4-aminobiphenyl in rat. I. Reaction ofN-hydroxy-4-aminobiphenyl with rat bloodin vivo

Cited by 10 publications

References 17 publications

Possible implications of doxycycline-rifampin interaction for treatment of brucellosis

Possible implications of doxycycline-rifampin interaction for treatment of brucellosis

Reactions of Nitrosoarenes with SH Groups

Use of a metabolic inhibitor to reduce dapsone‐dependent haematological toxicity

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