SINGLE-DOSE AND MULTIPLE-DOSE PHARMACOKINETICS OF CLARITHROMYCIN, A NEW MACROLIDE ANTIMICROBIAL

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy me tabolite were evaluated after single and multiple oral doses of 250 an d 500 mg of clarithromycin. Multiple-dose regimens used 12-hour dosing intervals for 7 doses. Plasma and urine concentrations were measured using high-performance liquid chromatography. Appearance of clarithrom ycin and its metabolite in plasma were rapid, as reflected by mean tim es to maximum plasma concentration ranging from 1.8 to 2.6 and 1.8 to 2.9 hours, respectively. The rises in clarithromycin peak plasma conce ntration (Cmax) and area under the plasma concentration versus time cu rve (AUC) were disproportionate to increase in dose, suggesting nonlin earity in parent compound pharmacokinetics. Clarithromycin terminal di sposition half-life (t1/2) also exhibited dose dependency, ranging fro m harmonic means of 2.7 to 4.8 hours. In contrast, based on Cmax AUC, and predicted/observed accumulation ratios, nonlinearity in metabolite pharmacokinetics was not observed. Plasma accumulation of metabolite occurred to a much lesser degree than that of the parent compound desp ite a substantially longer t1/2 for the metabolite (metabolite accumul ation ratios based on AUC dose 7/AUC dose 1: 250-mg regimen = 1.03 +/- 0.33, 500-mg regimen = 0.81 +/- 0.29, parent accumulation ratios: 250 -mg regimen = 1.64 +/- 0.47, 500-mg regimen = 1.65 +/- 0.69). This wou ld suggest that formation of this metabolite is capacity-limited and t hat this may in part account for the nonlinearity observed in clarithr omycin pharmacokinetics. Urinary excretion constituted a relatively im portant route of elimination of clarithromycin, with renal clearance a ccounting for 17 to 31% of apparent total body clearance.