Our objective was to study the steady-state plasma and intrapulmonary orally administered
ethambutol concentrations in healthy volunteers and subjects with
AIDS.
Ethambutol (15 mg/kg of
body weight) was administered orally once daily to 10 men with
AIDS, 10 healthy men, 10 women with
AIDS, and 10 healthy women. The mean (+/-standard deviation [SD]) CD4 cell count for the 20 subjects with
AIDS was (350 +/- 169) x 10(6) cells per liter. Blood was obtained for
drug assay 2 h after the last dose and at the completion of bronchoalveolar lavage, performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) was calculated by the
urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation.
Ethambutol was measured by a new, sensitive and specific liquid chromotography-mass spectrometry method. The presence of
AIDS, as defined in this study, or gender was without significant effect on the concentrations of
ethambutol in plasma at 2 or 4 h or in ELF at 4 h following the last dose. Plasma
drug concentrations (mean +/- SD) at 2 and 4 h were 2.1 +/- 1.2 and 2.1 +/- 0.8 microg/ml, respectively, and both values were not significantly different from the concentration of
ethambutol in ELF at 4 h (2.2 +/- 1.1 microg/ml). The concentration of
ethambutol was significantly greater in AC in all four groups (range, 44.5 +/- 15.6 to 82.0 +/- 39.4 microg/ml) than in ELF or plasma and was approximately 30 to 240 times the reported MIC for
ethambutol-susceptible strains of Mycobacterium tuberculosis. The AC
ethambutol concentration (mean +/- SD) in the smoking women (97.2 +/- 32.1 microg/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 +/- 16.8 microg/ml) combined (P < 0.05). Two- and 4-h concentrations of
ethambutol in plasma were not affected by
AIDS status or gender. The high AC/plasma and AC/ELF concentration ratios suggest that substantial antimycobacterial activity resides in these cells. The data confirm earlier observations of active transport ex vivo of
ethambutol into pulmonary macrophages.