In a double-blind, randomised, three-way cross-over study, eight healthy volunteers ingested daily for 4 days either 250 mg clarithromycin twice daily, 200 mg itraconazole once daily, or placebo. On day 4, each subject received a single dose of 0.6 mg kg-1 ropivacaine intravenously over 30 min. Ropivacaine and (S)-2',6'-pipecoloxylidide in venous plasma and urine samples were measured for up to 12 hours and 24 hours, respectively. There were no significant changes in the pharmacokinetic parameters of the parent ropivacaine after ingestion of clarithromycin or itraconazole. However, the peak plasma concentration and AUC of (S)-2',6'-pipecoloxylidide metabolite were significantly decreased in both the clarithromycin and itraconazole phases, compared with the placebo phase. The fraction of ropivacaine metabolised to (S)-2',6'-pipecoloxylidide excreted in urine was decreased in the itraconazole phase. Both clarithromycin and itraconazole inhibit the CYP3A4 mediated formation of (S)-2',6'-pipecoloxylidide from ropivacaine. With the doses used, itraconazole is a stronger inhibitor than clarithromycin. The interaction of clarithromycin with ropivacaine seems to be dose (concentration)-dependent.