In this study, our objective was to determine the steady-state intrapulmonary concentrations and pharmacokinetic parameters of orally administered linezolid in healthy volunteers. Linezolid (600 mg every 12 h for a total of five doses) was administered orally to 25 healthy adult male subjects. Each subgroup contained five subjects, who underwent bronchoscopy and bronchoalveolar lavage (BAL) 4, 8, 12, 24, or 48 h after administration of the last dose. Blood was obtained for drug assay prior to administration of the first dose and fifth dose and at the completion of bronchoscopy and BAL. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method, and the total number of alveolar cells (AC) was counted in a hemocytometer after cytocentrifugation. Linezolid was measured in plasma by a high-pressure liquid chromatography (HPLC) technique and in BAL specimens and AC by a combined HPLC-mass spectrometry technique. Areas under the concentration-time curves (AUCs) for linezolid in plasma, ELF, and AC were derived by noncompartmental analysis. Half-lives for linezolid in plasma, ELF, and AC were calculated from the elimination rate constants derived from a monoexponential fit of the means of the observed concentrations at each time point. Concentrations (means ؎ standard deviations) in plasma, ELF, and AC, respectively, were 7.3 ؎ 4.9, 64.3 ؎ 33.1, and 2.2 ؎ 0.6 g/ml at the 4-h BAL time point and 7.6 ؎ 1.7, 24.3 ؎ 13.3, and 1.4 ؎ 1.3 g/ml at the 12-h BAL time point. Linezolid concentrations in plasma, ELF, and AC declined monoexponentially, with half-lives of 6.9, 7.0, and 5.7 h, respectively. For a MIC of 4, the 12-h plasma AUC/MIC and maximum concentration/MIC ratios were 34.6 and 3.9, respectively, and the percentage of time the drug remained above the MIC for the 12-h dosing interval was 100%; the corresponding ratios in ELF were 120 and 16.1, respectively, and the percentage of time the drug remained above the MIC was 100%. The long plasma and intrapulmonary linezolid half-lives and the percentage of time spent above the MIC of 100% of the dosing interval provide a pharmacokinetic rationale for drug administration every 12 h and indicate that linezolid is likely to be an effective agent for the treatment of pulmonary infections.

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) ؋ 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 g/ml, respectively, and both values were not significantly different from the concentration of ethambutol in ELF at 4 h (2.2 ؎ 1.1 g/ml). The concentration of ethambutol was significantly greater in AC in all four groups (range, 44.5 ؎ 15.6 to 82.0 ؎ 39.4 g/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 g/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 ؎ 16.8 g/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.Ethambutol is an important orally administered drug that is used for the treatment of tuberculosis. It is recommended as a fourth drug with isoniazid, rifampin, and pyrazinamide (PZA) until the susceptibility of the organism is determined (7). The usual dose is 15 to 25 mg/kg of body weight administered as a single daily dose. The elimination half-life in humans is approximately 12 h (19). After administration of a single 25-mg/kg dose under fasting conditions, the mean maximum concentration of ethambutol in serum has been reported to be 4.5 g/ml, with a range of 1.8 to 6.9 g/ml, and the mean time to maximum concentration was 2.5 h, with a range of 1. 1122-1123, 1993). However, other reports have not confirmed this observation (8,11,12,18,26). The effects of gender and AIDS on the steady-state plasma and pulmonary kinetics of ethambutol have not been reported.Ethambutol is mo...

The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volunteers who received a single, oral dose of rifapentine (600 mg). Subgroups of five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL) at timed intervals following drug administration. Drug concentrations, including the concentration of the primary metabolite 25-desacetyl rifapentine, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pressure liquid chromatography. The concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The concentration-time data were fit to two-compartment (plasma) or one-compartment (AC and ELF) models. The peak concentrations in plasma, ELF, and AC, 26.2, 3.7, and 5.3 g/ml, respectively, occurred at 5, 5, and 7 h after drug administration, respectively. The half-lives and areas under the curve for plasma, ELF, and AC were 18.3 h and 520 g ⅐ h/ml, 20.8 h and 111 g ⅐ h/ml, and 13.0 h and 133 g ⅐ h/ml, respectively. Although the intrapulmonary rifapentine concentrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis (0.5 g/ml) for the 48-h observation period. These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.Rifapentine is an orally administered rifamycin derivative that has antituberculous activity and that is similar to rifampin (11,12,16,27). The MICs for sensitive strains are usually in the range of 0.03 to 0.12 mg/liter, and MICs for resistant strains are Ն8 mg/liter (15). Cross-resistance between rifapentine and rifampin is virtually complete (15). Cross-resistance between rifapentine and rifampin is virtually complete (15). Rifapentine has a longer elimination half-life than rifampin, allowing the possibility of less frequent (twice-or once-weekly) administration (17).There have been no previous reports of the intrapulmonary concentrations or pharmacokinetics of rifapentine in humans. The purpose of this study was to compare the concentrations of rifapentine in plasma, alveolar cells (ACs), and epithelial lining fluid (ELF) of normal volunteers and to compare the drug's pharmacokinetics in these three compartments. MATERIALS AND METHODSSubjects. The protocol was approved by the Human Research Committee of the University of California, San Francisco. Written informed consent was obtained from each subject by an experienced research nurse. Subjects were required to be 18 to 45 years of age. If the subjects were female, they were required to be nonlactating and not pregnant and to agree to use adequate contraception (e.g., barrier methods or abstinence) during the study and for 2 weeks following completion of the study. Women using oral contraceptives were required to agree to use a barrier method in addition for 1 month following the study. Subjects who were lactating or pregnant, had a history of intolerance to rifamycin dr...

The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 ؎ 1.60 g/ml [mean ؎ standard deviation; n ‫؍‬ 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 ؎ 3.50 g/ml) or ACs (2.61 ؎ 5.01 g/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 g/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 g/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 g/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.Isoniazid is an essential drug in the treatment of tuberculosis. For humans without tuberculosis who received a single 250-mg oral dose of isoniazid, elimination half-lives have been reported to be 1.2 and 3.3 h in fast and slow acetylators, respectively, and peak concentrations in plasma (at 1 h postdosing) have been reported to be 2.44 and 3.64 g/ml, respectively (25) 1993). However, this effect was not demonstrated in Kenyan patients, in whom concentrations in plasma were not different among individuals with or without AIDS or w...

The absorption of oral rifampicin was not affected by sex or AIDS. Plasma and alveolar cell concentrations were not significantly different, were both greater than ELF concentrations, and were adequate to inhibit Mycobacterium tuberculosis. Considerable interpatient variability was detected despite witnessed drug administration. The clinical significance of these findings is unknown but merits further investigation.