Intrapulmonary pharmacokinetics of clarithromycin and of erythromycin

Abstract

The intrapulmonary pharmacokinetics of orally administered clarithromycin (500 mg every 12 h for five doses) or erythromycin (250 mg every 6 h for nine doses) were studied in 32 healthy adult volunteers. Four of the subjects, two in the clarithromycin group and two in the erythromycin group, were smokers. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed at 4, 8, 12, 24, and 48 h after administration of the last dose of clarithromycin and at 4, 8, and 12 h after administration of the last dose of erythromycin. Clarithromycin was measured by high-performance liquid chromatography, and erythromycin was measured by a microbiological assay. No systemic sedation was used. There were no major adverse events. The concentrations of antibiotics in epithelial lining fluid (ELF) were calculated by the urea dilution method. The volumes (mean ؎ standard deviation) of ELF were 1.9 ؎ 2.0 ml and 1.5 ؎ 0.7 ml in the clarithromycin and erythromycin groups, respectively (P > 0.05). There was no effect of smoking on the amount of bronchoalveolar lavage fluid recovered, the volume of ELF, or the number of erythrocytes present in the lavage fluid (P > 0.05 for all comparisons). The total number of alveolar cells, however, was almost threefold greater in the smokers versus that in the nonsmokers (P < 0.05). Clarithromycin was concentrated in ELF (range, 72.1 ؎ 73.0 g/ml at 8 h to 11.9 ؎ 3.6 g/ml at 24 h) and alveolar cells (range, 505.8 ؎ 293.1 g/ml at 4 h to 17.0 ؎ 34.0 g/ml at 48 h). 14-(R)-Hydroxyclarithromycin was also present in these compartments, but at lower concentrations than the parent compound. The concentrations of erythromycin in ELF and alveolar cells were low at 4, 8, and 12 h following the last dose of drug (range, 0 to 0.8 ؎ 0.1 g/ml in ELF and 0 to 0.8 ؎ 1.3 g/ml in alveolar cells). The clinical significance of any antibiotic concentrations in these compartments is unclear. The data suggest, and we conclude, that clarithromycin may be a useful drug in the treatment of pulmonary infections, particularly those caused by intracellular organisms.Clarithromycin is a semisynthetic macrolide antibiotic that contains a 14-member lactone ring (32). It is active against Streptococcus pneumoniae, Haemophilus influenzae group A streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Moraxella catarrhalis, Chlamydia pneumoniae, Mycobacterium pneumoniae, Toxoplasma gondii, Listeria monocytogenes, legionellae, atypical mycobacteria, and Mycobacterium leprae (2,7,19,22,23,25,28,31,38,42). Like other macrolides, clarithromycin is concentrated in phagocytic cells (5,6,9,30), and it is active against intracellularly growing bacteria (1, 15, 36).The kinetics of clarithromycin are nonlinear (11,13,16). The apparent half-life varies with the dose and ranges from 2 to 6 h for clarithromycin and from 2 to 9 h for its 14-(R)-hydroxyclarithromycin metabolite after the administration of doses of 100 to 1,200 mg given orally. The elimination half-life of erythromycin is approximately 1 to 6 h after oral administrat...

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

“…The urea concentration in BALF was first corrected for possible contamination with urea from blood using the method described previously 64 65 The concentration of ALX-0171 in epithelial lining fluid was calculated as described in different studies 64-67 using the following formula: ELF [ALX-0171] = BALF [ALX-0171] X ([Urea Plasma ]/[Urea BALF Corr ]). Where: ELF [ALX-0171] is the ALX-0171 concentration in epithelial lining fluid, BALF [ALX-0171] is the ALX-0171 concentration in recovered BALF, [Urea Plasma ] is the concentration of urea in plasma and [Urea BALF Corr ] is the corrected urea concentration in BALF.…”

Intrapulmonary Pharmacokinetics of Linezolid

“…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.…”

Evaluation of macrolides for possible use against multidrug-resistantMycobacterium tuberculosis

“…Despite high MIC values, some bronchopulmonary pharmacokinetic studies demonstrated that high concentrations of CLR were achieved in alveolar macrophages and epithelial lining fluid (ELF), with high ratios of concentrations in ELF and alveolar macrophages compared with that in plasma assessed in healthy volunteers [74][75][76]. These results suggest that high concentrations of CLR are achieved in ELF and alveolar macrophage cells, which exceed the in vitro MIC values by several fold.…”