Steady-state plasma and bronchopulmonary characteristics of clarithromycin extended-release tablets in normal healthy adult subjects.
OBJECTIVE
The steady-state concentrations of clarithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL). Concentrations of the major metabolite, 14-hydroxyclarithromycin, were also determined in plasma and AM.


METHODS
Forty-two healthy, non-smoking adult subjects (age: 18-54 years; 19 females, 23 males) received oral clarithromycin extended-release formulation (1000 mg once daily for five consecutive days). Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, 24 or 48 h after the last administered dose of clarithromycin. In addition, three subjects who did not take clarithromycin served as controls and underwent bronchoscopy at 0 h. Drug concentrations in plasma, ELF, and AM were determined by high-performance liquid chromatography.


RESULTS
Clarithromycin was extensively concentrated in ELF [range of mean (+/-s.d.) concentrations: 6.38 +/- 3.92 to 11.50 +/- 6.65 mg/L] and AM (127.0 +/- 61.5 to 573.8 +/- 309.3 mg/L) than simultaneous plasma concentration (0.75 +/- 0.31 to 2.22 +/- 0.72 mg/L). The ranges of mean (+/-s.d.) concentrations of 14-hydroxyclarithromycin in plasma and AM were 0.52 +/- 0.29 to 0.80 +/- 0.31 mg/L and 22.1 +/- 13.5 to 49.5 +/- 16.2 mg/L, respectively.


CONCLUSIONS
Once-daily dosing of extended-release formulation clarithromycin 1000 mg produced significantly (P < 0.05) higher steady-state concentrations of clarithromycin in ELF (2-14 times) and AM (50-700 times) compared to simultaneous plasma concentrations throughout the 24 h period after drug administration. The 14-hydroxy metabolite of clarithromycin achieved significantly (P < 0.05) higher steady-state concentrations in AM (18-180 times) compared with concurrent plasma concentrations.
Gotfried
Mark H
MH
Pulmonary Associates, University of Arizona, Phoenix, AZ, USA.
Danziger
Larry H
LH
Rodvold
Keith A
KA
D000328:Adult; D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D001980:Bronchi / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002851:Chromatography, High Pressure Liquid; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D014508:Urea / Q000097:blood
D000900:Anti-Bacterial Agents; D003692:Delayed-Action Preparations; D014508:Urea; D017291:Clarithromycin