A simple method for determining acetylator phenotype using isoniazid.

Hutchings, A.; Routledge, PA

doi:10.1111/j.1365-2125.1986.tb02897.x

Cited by 33 publications

(24 citation statements)

References 8 publications

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“…As another means to assess acetylator phenotype, the metabolic ratio of acetylisoniazid concentration to isoniazid concentration at 3 h postdose was calculated. Patients with a ratio above 1.5 were considered fast/intermediate metabolizers, and patients with a ratio below 1.5 were considered slow metabolizers (21). In addition, we also explored a metabolic ratio of 0.55 at 3 h postdose as a cutoff to distinguish fast/ intermediate from slow metabolizers, as this evolved from a study in African patients (23).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of First-Line Tuberculosis Drugs in Tanzanian Patients

Tostmann

Mtabho

Semvua

et al. 2013

Antimicrob Agents Chemother

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East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling. In 20 adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10, and 24 h after observed drug intake with food to estimate the areas under the curve from 0 to 24 h (AUC 0 -24 ) and peak plasma concentrations (C max ) of isoniazid, rifampin, pyrazinamide, and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 h postdose. The geometric mean AUC 0 -24 s were as follows: isoniazid, 11.0 h · mg/liter; rifampin, 39.9 h · mg/liter; pyrazinamide, 344 h · mg/liter; and ethambutol, 20.2 h · mg/liter. The C max was below the reference range for isoniazid in 10/19 patients and for rifampin in 7/20 patients. In none of the patients were the C max s for pyrazinamide and ethambutol below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients. A substantial proportion of patients had an isoniazid and/or rifampin C max below the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such a drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies.T he pharmacokinetic properties of tuberculosis (TB) drugs are well described, especially in Caucasian populations (1, 2). Pharmacokinetic data from East Africa are limited, especially data that are based on intensive pharmacokinetic sampling during the full dosing interval. Such intensive pharmacokinetic sampling enables an accurate assessment of the total exposure to TB drugs (area under the time-versus-plasma concentration curve from 0 to 24 h [AUC 0 -24 ]) and the peak plasma concentration (C max ) in individual patients. Large interpatient variability in these key pharmacokinetic parameters of TB drugs generally exists (1). As a result, a proportion of patients achieve drug concentrations that are below the reference range for TB drugs. Several studies have shown that such lower exposures to TB drugs are associated with a suboptimal response (3-8) A recent study showed that pharmacokinetic variability to just a single drug in the multidrug TB drug regimen is associated with treatment failure and acquired drug resistance (9, 10).On the other hand, unduly high exposures may cause toxicity and interruption of TB treatment. It is therefore important to have more knowledge on the pharmacokinetic properties of TB treatment in populations from East Africa, as a high TB incidence and a high TB mortality are found in this region (11). HIV infection (12-14) and malnutrition (15) have been associ...

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of First-Line Tuberculosis Drugs in Tanzanian Patients

Tostmann

Mtabho

Semvua

et al. 2013

Antimicrob Agents Chemother

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“…Acetylator status for isoniazid was determined phenotypically by calculating the metabolic ratio (MR) for isoniazid (acetylisoniazid C 2 h /isoniazid C 2 h ), with fast acetylators having MRs Ն 1.5 and slow acetylators having MRs Ͻ 1.5 (21).…”

Section: Methodsmentioning

confidence: 99%

Isoniazid, Rifampin, and Pyrazinamide Plasma Concentrations in Relation to Treatment Response in Indonesian Pulmonary Tuberculosis Patients

Burhan

Ruesen

Ruslami

et al. 2013

Antimicrob Agents Chemother

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f Numerous studies have reported low concentrations of antituberculosis drugs in tuberculosis (TB) patients, but few studies have examined whether low drug concentrations affect TB treatment response. We examined steady-state plasma concentrations of isoniazid, rifampin, and pyrazinamide at 2 h after the administration of drugs (C 2 h ) among 181 patients with pulmonary tuberculosis in Indonesia and related these to bacteriological response during treatment. C 2 h values below reference values for either isoniazid, rifampin, or pyrazinamide were found in 91% of patients; 60% had at least two low C 2 h concentrations. The isoniazid C 2 h was noticeably lower in fast versus slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P < 0.001). At the end of treatment, 82% of the patients were cured, whereas 30 patients (17%) had dropped out during the study, and 2 patients (1%) failed treatment. No association was found between C 2 h concentrations and sputum culture results at 8 weeks of treatment. Post hoc analysis showed that patients with low pyrazinamide C 2 h (P ‫؍‬ 0.01) and patients with large extensive lung lesions (P ‫؍‬ 0.01) were at risk of at least one positive culture at week 4, 8, or 24/32. Antituberculosis drug concentrations were often low, but treatment response was nevertheless good. No association was found between drug concentrations and 8 weeks culture conversion, but low pyrazinamide drug concentrations may be associated with a less favorable bacteriological response. The use of higher doses of pyrazinamide may warrant further investigation. G enerally, first-line treatment of drug-susceptible tuberculosis (TB) is highly effective. However, a number of patients do not respond adequately to treatment, develop drug resistance or experience a relapse of TB after completion of treatment. Inadequate exposure to anti-TB drugs may constitute one of the factors underlying suboptimal treatment response (1, 2). Among adults, low plasma concentrations of anti-TB drugs have been found in patients with HIV infection, gastrointestinal tract disorders, high body weight, male gender, or diabetes mellitus (DM) (3-11) and in fast acetylators for isoniazid (12). Low plasma concentrations can also result from interindividual variability in drug absorption, metabolism, or excretion (3, 13). Some studies have reported associations between low concentrations of anti-TB drugs and poor treatment response (1-3, 14), although this was not found in other studies (7,15). In a recent study performed in a preclinical model, pharmacokinetic variability appeared to be more important in the emergence of multidrug-resistant tuberculosis (MDR-TB) than nonadherence (16). Furthermore, a systematic review showed that pharmacokinetic variability to isoniazid in multi-drug TB regimens is significantly associated with therapy failure and acquired drug resistance (17).Nevertheless, the number of studies examining the relation between plasma concentrations of anti-TB drugs and treatment response remains limited and the majority of them inves...

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“…a type II error has been made). Nevertheless, no subject changed his or her phenotype, determined either by isoniazid halflife of elimination or by the ratio of acetyl isoniazid to isoniazid in the 3 h sample (Hutchings & Routledge, 1986). It is therefore unlikely that any small effect missed in this study will be clinically relevant in view of the marked differences attributable to genetic influences of isoniazid metabolism.…”

Section: Discussionmentioning

confidence: 91%

“…Similarly, the acetyl isoniazid/isoniazid (AcINH/INH) ratio in the 3 h sample did not differ significantly between the hyperthyroid and euthyroid states. All patients remained within the same phenotypic classification before and after treatment (five fast, five slow) whether this was assessed by half-life or AcINH/INH ratio (Hutchings & Routledge, 1986). …”

Section: Introductionmentioning

confidence: 99%

The effect of thyrotoxicosis on isoniazid acetylation.

Littley

Hutchings

Spragg

et al. 1988

Brit J Clinical Pharma

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Isoniazid acetylation was assessed in 10 thyrotoxic patients before and after standard antithyroid therapy. The group contained five fast and five slow acetylators and all remained within the same phenotypic classification when rendered euthyroid. There was no significant change in the elimination half‐life of isoniazid between thyrotoxicosis and euthyroidism for the group as a whole or for fast and slow acetylators considered separately. Thyrotoxicosis does not appear to be an important determinant of isoniazid acetylation in man.

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A simple method for determining acetylator phenotype using isoniazid.

Abstract: A comparison was made between the results of acetylator phenotyping by isoniazid (INH) half-life measurements based on samples taken for 6 h after a single oral dose (200 mg

Cited by 33 publications

References 8 publications

Pharmacokinetics of First-Line Tuberculosis Drugs in Tanzanian Patients

Pharmacokinetics of First-Line Tuberculosis Drugs in Tanzanian Patients

Isoniazid, Rifampin, and Pyrazinamide Plasma Concentrations in Relation to Treatment Response in Indonesian Pulmonary Tuberculosis Patients

The effect of thyrotoxicosis on isoniazid acetylation.

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