The Absorption, Excretion, and Metabolic Fate of Ethambutol in Man<sup>1</sup>

Peets, Edwin A.; Sweeney, William M.; Place, Virgil A.; Buyske, D. A.

doi:10.1164/arrd.1965.91.1.51

Cited by 81 publications

(26 citation statements)

References 5 publications

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“…The metabolism of ETB to EDBA has been known since the 1960s (33), and in this study we have been able to demonstrate an addition to a downstream metabolic step of EDBA. ETB is an important first-line drug for TB treatment and used for treatment of patients infected with Mycobacterium avium complex (MAC) organisms, which reports a treatment failure rate of 40% to 60% (34).…”

Section: Discussionsupporting

confidence: 54%

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

Das

Arya

Debnath

et al. 2016

Antimicrob Agents Chemother

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Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n ‫؍‬ 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs, viz., isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2=-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ؎ 3.03 and 6.09 ؎ 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites.

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Section: Discussionsupporting

confidence: 54%

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

Das

Arya

Debnath

et al. 2016

Antimicrob Agents Chemother

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“…Ethambutol's major urinary meta bolites are the microbiologically inactive dialdehyde and dicarboxylic acid derivatives [117]. The elimination half-life of ethambutol during the first 12 h after dosage is about 4 h in patients with normal renal function (table 9), suggesting that in complete renal failure half-lives could be increased to about 20 h (table 11).…”

Section: Ethambutol: Pharmacologymentioning

confidence: 99%

Chemotherapy of Tuberculosis for Patients with Renal Impairment

Ellard¹

1993

Nephron

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“…EMB is eliminated mainly via renal filtration and active tubular secretion; approximately 50 to 70% and 70 to 84% of oral and intravenous doses, respectively, are recovered unchanged in the urine of subjects with normal renal function (6,18,19,25). EMB has a low plasma protein binding, with an unbound fraction of 70 to 80% (18).…”

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confidence: 99%

Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

Jönsson

Davidse

Wilkins

et al. 2011

Antimicrob Agents Chemother

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Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.In order to optimize treatment regimens, there is an urgent need to critically evaluate the pharmacokinetics and corresponding effects of the antituberculosis drugs among patients with tuberculosis. Population pharmacokinetic modeling is considered an efficient means to summarize data in terms of typical parameter estimates, effects of covariates (e.g., body weight, sex, and gender), and unexplained variability. Furthermore, population pharmacokinetic models are valuable for simulation purposes and enable alternative dose regimens for subpopulations aiming at specific pharmacokinetic target levels to be assessed to establish more effective treatment. The present analysis was designed to describe the population pharmacokinetics of ethambutol (EMB) in a South African patient population, including the characterization of interindividual variability (IIV) and interoccasion variability (IOV) and exploration of the causes of variability, which have not been addressed in previous models (27,39).EMB is a bacteriostatic agent with a mechanism of action that has been suggested to occur by inhibition of mycobacterial cell wall synthesis. The primary role of EMB in the first-line four-drug antitubercular regimen (i.e., EMB in combination with rifampin, isoniazid, and pyrazinamide) is to protect aga...

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The Absorption, Excretion, and Metabolic Fate of Ethambutol in Man¹

Cited by 81 publications

References 5 publications

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

Chemotherapy of Tuberculosis for Patients with Renal Impairment

Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

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The Absorption, Excretion, and Metabolic Fate of Ethambutol in Man1

Cited by 81 publications

References 5 publications

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

Chemotherapy of Tuberculosis for Patients with Renal Impairment

Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

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The Absorption, Excretion, and Metabolic Fate of Ethambutol in Man¹