Effects of AIDS and Gender on Steady-State Plasma and Intrapulmonary Ethionamide Concentrations

Abstract

Ethionamide, 250 mg every 12 h for a total of nine doses, was administered to 40 adult volunteers (10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women). Blood was obtained for drug assay prior to administration of the first dose, 2 h after the last dose, and at the completion of standardized bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Ethionamide was measured in epithelial lining fluid (ELF) and alveolar cells (AC) using a new mass spectrometric method. The presence of AIDS or gender was without significant effect on the concentrations of ethionamide in plasma, AC, or ELF. Plasma concentrations (mean ؎ standard deviation [SD]) were 0.97 ؎ 0.65 and 0.65 ؎ 0.35 g/ml at 2 and 4 h after the last dose, respectively, and both values were significantly greater than the concentration of ethionamide in AC (0.38 ؎ 0.47 g/ml) (P < 0.05). The concentration of ethionamide was significantly greater in ELF (5.63 ؎ 3.8 g/ml) than in AC or plasma at 2 and 4 h and was approximately 10 to 20 times the reported MIC for ethionamide-susceptible strains of Mycobacterium tuberculosis. For all 40 subjects, the ELF/plasma concentration ratios (mean ؎ SD) at 2 and 4 h were 8.7 ؎ 11.7 and 9.7 ؎ 5.6, respectively. We conclude that the absorption of orally administered ethionamide, as measured in this study, was not affected by gender or the presence of AIDS. Ethionamide concentrations were significantly greater in ELF than in plasma or AC, suggesting that substantial antimycobacterial activity resides in this compartment.Ethionamide is a second-line, orally administered drug that is used for the treatment of tuberculosis. It is often combined with other antituberculous agents for the treatment of multiple-drug-resistant organisms. The usual dose is 250 to 500 mg two to four times per day (1, 21). The daily dose is limited by gastrointestinal toxicity. The elimination half-life in humans is approximately 2 to 3 h (18,19,22). Peak plasma concentrations occur at approximately 2 h postdosing and have been reported to be between 0.6 and 1.9 g/ml following an oral dose of 250 mg (11, 18) and 2.2 g/ml following an oral dose of 500 mg Ethionamide is active against tubercle bacilli that are growing within human macrophages (24). The in vivo penetration of ethionamide into pulmonary macrophages and epithelial lining fluid (ELF) in humans has not been reported. We (7-9) and others (2-4) have developed techniques for the measurement, in vivo, of the concentration of drugs in pulmonary ELF and alveolar cells (AC). The purpose of this study was to compare the steady-state plasma and intrapulmonary ethionamide concentrations in healthy volunteers and men and women with AIDS. MATERIALS AND METHODSStudy design and subjects. The investigation was prospective and nonblinded. After giving informed consent, subjects underwent a medical history, physical examination, purified protein derivative skin test, and baseline laboratory testing including complete blood count, platelet count, blood urea ni...

Intrapulmonary Pharmacokinetics of Linezolid

“…The linezolid concentrations in plasma (means Ϯ SDs) determined at the times of bronchoscopy (4,8,12,24, and 48 h after the fifth dose) ranged from 15.5 Ϯ 24.2 g/ml (C max in plasma) to 0.2 Ϯ 0.2 g/ml (C min in plasma) and declined monoexponentially (R ϭ Ϫ0.99) with a t 1/2 of 6.9 h. The mean plasma drug concentrations, SDs, and minima and maxima for each time point are summarized in Table 2. The AUC 0-12 and AUC 0-24 for plasma following the fifth dose were 132.2 and 204.2 g·h/ml, respectively ( Fig.…”

“…Urea was measured in BAL fluid supernatant by a modified enzymatic assay (kit UV-66 for measurement of urea nitrogen in the blood; Sigma, St. Louis, Mo.) as previously reported (8)(9)(10)(11)(12)(13). The assay was linear (R 2 ϭ 0.99) for concentrations of urea in BAL fluid from 0.047 to 0.750 mg/dl.…”

“…The amount of ELF recovered was calculated by the urea dilution method as described by Rennard et al (22) and as reported from other previous pulmonary pharmacokinetic studies (8)(9)(10)(11)(12)(13). The concentration of urea in serum was analyzed by the clinical laboratory at the University of California, San Francisco, by a coupled urease-glutamate dehydrogenase enzymatic method modified by Boehringer Mannheim Corporation (Indianapolis, Ind.)…”

“…Standardized bronchoscopy and bronchoalveolar lavage (BAL) (8)(9)(10)(11)(12)(13) were performed in the Clinical Trials Center at 4, 8, 12, 24, or 48 h after the administration of the last dose. Blood pressure, heart rate, respiratory rate, and temperature were recorded prior to, and at the completion of, bronchoscopy and as clinically indicated following the procedure.…”

“…Researchers (1)(2)(3)(4)(5)(8)(9)(10)(11)(12)(13) have developed techniques for the measurement, in vivo, of the concentrations of drugs in ELF and AC. The purpose of this study was to determine the steady-state intrapulmonary concentrations and intrapulmonary pharmacokinetic parameters of orally administered linezolid in healthy volunteers.…”