A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man

Jenner, Peter; Ellard, G. A.; Gruer, P J; Aber, V. R.

doi:10.1093/jac/13.3.267

Cited by 50 publications

(27 citation statements)

References 5 publications

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“…Mean C max values ranging from 2.2 to 2.6 g/ml, with corresponding average T max values of 1.5 to 3 h, have been reported following a single 500-mg dose of ETA taken on an empty stomach (10)(11)(12)(13)19) or with fruit juice (26). For AUC 0-ϱ , we have previously found a similar value of 10.3 g ⅐ h/ml (19).…”

Section: Discussionmentioning

confidence: 99%

“…Considerable variability has also been observed in the individual plasma ETA concentrations of samples drawn at 1, 3 and 5 h postdosing for 20 subjects treated for pulmonary tuberculosis (26). ETA may undergo first-pass metabolism that could contribute to this variability (5,11,13,25). The wide range of body weights in our subjects also might have contributed to the variability.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of Ethionamide Administered under Fasting Conditions or with Orange Juice, Food, or Antacids

Auclair¹,

Nix

Adam

et al. 2001

Antimicrob Agents Chemother

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This study was conducted in order to (i) determine the effect of food, orange juice, or antacids on the absorption of a single oral 500-mg dose of ethionamide (ETA) in healthy volunteers, including an assessment of bioequivalence, and (ii) determine ETA population pharmacokinetic (PK) parameters. The pharmacokinetics of ETA in serum was determined for 12 healthy males and females in a randomized, four-period crossover study. Volunteers received single 500-mg doses of ETA either on an empty stomach (reference) or with food, orange juice, or antacids. Serum samples were collected for 48 h and assayed by high-performance liquid chromatography. Data were analyzed by noncompartmental and population methods. Mean test/reference ratios and 90% confidence intervals were determined. No statistically significant differences were seen in the maximum concentration of ETA (C max ), time to maximum concentration (T max ), or area under the concentration-time curve from 0 h to infinity (AUC 0-ؕ ) between the four treatments (P > 0.05 by analysis of variance). The least-squares mean ratios (with confidence intervals in parentheses) for C max were 105% (81.2 to 135%) after orange juice, 94% (72.8 to 121%) after food, and 88% (68.4 to 114%) after antacids. The least-squares mean ratios (with confidence intervals is in parentheses) for AUC 0-ؕ were 91% (72.7 to 115%) after orange juice, 96% (76.4 to 121%) after food, and 95% (75.5 to 120%) after antacids. The mean T max was slightly prolonged following antacid or food administration (2.3 to 2.6 h) compared to administration on an empty stomach or with juice (1.7 to 1.9 h). The median population PK parameters were as follows: K a ‫؍‬ 0.37 to 0.48 h ؊1 , V/F ‫؍‬ 2.0 to 2.8 liters/kg, CL/F ‫؍‬ 56.5 to 72.2 liters/h, and terminal half-life ‫؍‬ 1.7 to 2.1 h, where K a is the absorption rate constant, V is the volume of distribution, and CL is clearance. The PK behavior of ETA was not significantly modified by the different conditions studied. Mean ratios for AUC ranged from 0.91 to 0.96 for the orange juice, food, and antacid treatments, indicating a minimal effect on relative bioavailability. ETA can, therefore, be administered with food if tolerance is an issue.Ethionamide (ETA) is a bacteriostatic, isonicotinic acidderived antituberculosis agent (10, 28). It is used in combination for the treatment of clinical tuberculosis that has failed to respond to adequate first-line therapy (1). Very limited information exists in the literature regarding the pharmacokinetics (PK) of ETA in healthy volunteers or in patients with tuberculosis. ETA is often administered with meals to reduce gastrointestinal intolerance (1). However, to our knowledge, the effects of food, as well as those of antacids or acidic beverages on the PK of ETA have not been evaluated in a crossover study. We have previously demonstrated that food has minimal effect on the absorption of ethambutol and pyrazinamide, while antacids should be avoided near the time of ethambutol dosing (17, 18). Similarly, we have found that ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Ethionamide Administered under Fasting Conditions or with Orange Juice, Food, or Antacids

Auclair¹,

Nix

Adam

et al. 2001

Antimicrob Agents Chemother

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“…H is noteworthy that there is a linear relationship between mouse dietary concentrations of ethionamide and resultant serum levels, 0·02% in diet yielding mouse serum levels of 0' 1 Ilg/ml and 0·05% in diet yielding mouse serum levels of 0·2 Ilg/ ml. 1 2 In man 500 mg ethionamide results in peak serum levels of 3 Ilg/ml, [14][15][16] which is more than 10-fo ld greater than the minimal bactericidal serum concentration established for the studied strain, and has a half-life of2 hr. Owing to gastrointestinal toxicity in man, ethionamide I g/day is poorly tolerated, 500 mg/day better tolerated, and 250 mg/day well tolerated,I7.18 Thus the therapeutic index for ethionamide is quite narrow, and if the relatively low levels of ethionamide required for killing the studied strain can be substantiated as representative, ethionamide doses of250 mg/day or even less might be sufficient to treat leprosy.…”

Section: Discussionmentioning

confidence: 99%

The killing ofMycobacterium lepraein mice by various dietary concentrations of clofazimine and ethionamide

Rh¹

1987

Leprosy Review

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SummaryThe bactericidal activity for Mycobacterium lep rae in mice of a range of dietary concentrations of clofazimine and ethionamide was studied by the proportional bactericidal technique. The 2 highest concentrations of clofazimine studied, 0·0 I % and 0·003 % were respectively 99·6 ± O· 2 % and 98 ± 1·0% bactericidal. Though less killing was afforded by 0·00 1 % and 0·000 1 % clofazi mine, even the latter concentration retained significant bactericidal activity (84 ± 10% bactericidal). The minimal bact e ricidal dietary concentration of ethionamide was fo und to be approximately 0·02% (68 ± 13% bactericidal). Higher concentrations of ethionamide , 0·05% and greater, were consistently more active, at least 95 ± 3% bactericidal. It is noteworthy in these studies that significant bactericidal activity of both clofazimine and ethionamide was retained at lower dietary concentrations than had been demonstrated previously.Actual bactericidal activity against Mycobacterium leprae appears critical in the therapy of lepromatous leprosy. Recently results' were presented quantifying the killing of M. leprae in mice by a wide range of dietary concentrations of dapsone and rifampicin. Previous work2 in this regard had evaluated only high dietary concentrations of these and other agents which yield steady state levels corresponding to peak levels experienced by patients undergoing therapy. The evaluation of the killing of M. leprae by lower dietary concentrations that result in levels that are also experienced by patients had not previously been evaluated by these same methods. Since clofazimine and ethionamide are the only other antimicrobial agents that are widely used to treat leprosy,3 we studied these 2 antimicrobial agents in a similar manner.Both clofazimine and ethionamide have been demonstrated to be bactericidal for M. leprae infected mice at high dietary levels. Clofazimine 0·003% and 0·01 % in mouse food was previously fo und to be respectively 96-99% and 98% bactericidal,2 while ethionamide 0· 1 % and 0·2% was fo und respectively 98·6% and 97·4% bactericidal.2 Clofazimine accumulates in skin, resulting in a dose-related red-black discolouration which makes the drug unacceptable to some patients. If the dosage of clofazimine could be reduced without loss of significant antimicrobial potency, this would certainly be advantageous. Ethionamide is not well tolerated in a significant number of patients because of dose-dependent gastrointestinal intolerance, is hepatoxic, especially when combined

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“…For 25 years, the main research involving ETH was focused on the type of metabolites formed [18][19][20][21][22][23][24][25][26][27][28], starting, thus, the study of ETH metabolism. During this period the principal metabolite identified was ethionamide sulphoxide (4, Fig.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of the Antituberculosis Drug Ethionamide

Vale

Gomes²,

Santos³

2012

CDM

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Ethionamide (ETH) is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant Mycobacterium. Although ETH is a structural analogue of isoniazid (INH), both are pro-drugs that need to be activated by mycobacterial enzymes to exert their antimicrobial activity. ETH mechanism of action is thought to be identical to INH although the pathway of activation is distinct from that of INH. ETH is activated by an EthA enzyme, leading to the formation of an Soxide metabolite that has considerably better activity than the parent drug. This review comprehensively examines the aspects related with the metabolism of ETH since its discovery up to today.

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A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man

Cited by 50 publications

References 5 publications

Pharmacokinetics of Ethionamide Administered under Fasting Conditions or with Orange Juice, Food, or Antacids

Pharmacokinetics of Ethionamide Administered under Fasting Conditions or with Orange Juice, Food, or Antacids

The killing ofMycobacterium lepraein mice by various dietary concentrations of clofazimine and ethionamide

Metabolism of the Antituberculosis Drug Ethionamide

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