Effect of itraconazole on the pharmacokinetics of bupivacaine enantiomers in healthy volunteers.

We studied seven healthy volunteers given itraconazole 200 mg orally or placebo, once daily for 4 days, in a crossover study. On day 4, racemic bupivacaine 0.3 mg kg-1 was given i.v. over 60 min and venous plasma samples were collected for 23 h. Plasma concentrations of R- and S-bupivacaine, itraconazole and hydroxyitraconazole were measured. Itraconazole reduced the clearance of R-bupivacaine by 21% (P < 0.05) and that of S-bupivacaine by 25% (P < 0.05), while it had no significant effect on other pharmacokinetic variables of the enantiomers. Reduction of bupivacaine clearance by itraconazole probably increases the steady-state concentration of bupivacaine enantiomers by 20-25%. This should be taken into account in the concomitant use of bupivacaine and itraconazole, although the interaction seems to be of limited clinical significance.