The pharmacokinetics of clarithromycin and its 14-OH metabolite

Abstract

Clarithromycin has been administered to 486 subjects in 23 different Phase I studies. Absorption of clarithromycin is rapid and peak concentrations are reached within 2 h of oral dosing. Bioavailability of clarithromycin is c. 50% after oral dosing. However, additional clarithromycin is absorbed and converted into 14-OH-clarithromycin in the liver before entering the systemic circulation. The antimicrobial activity of 14-OH-(R)-clarithromycin, if anything, is superior to that of the parent compound, so that the total absorption of biologically active substance is more than 50% of the administered dose. Peak serum concentrations after oral administration of a 250 mg, film-coated tablet of clarithromycin are 1.5 mg l-1 clarithromycin and 0.8 mg l-1 of 14-OH-(R)-clarithromycin. Clarithromycin is 72% bound to plasma proteins at a concentration of 0.45 mg l-1 but binding decreases with increasing concentration of clarithromycin. Concentrations of clarithromycin in lung are approximately five-fold greater than serum concentrations. Clarithromycin is metabolized in the liver and in the stomach. Approximately 22% of an oral dose is recovered as parent compound, 18% in the urine and 4% in the faeces. Clearance of clarithromycin decreases with increasing dose, probably because of saturable hepatic metabolism. There is a progressive increase in serum concentrations of clarithromycin and 14-OH-(R)-clarithromycin with renal impairment so that doses may need to be reduced in severe impairment (glomerular filtration rate less than 30 ml min-1). No effect of age on clarithromycin clearance has been demonstrated when clarithromycin clearance is corrected for creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)