The effect of erythromycin, fluvoxamine, and their combination on the pharmacokinetics of ropivacaine

We studied the effect of fluvoxamine and erythromycin on the pharmacokineti cs of ropivacaine in a double-blinded, randomized, four-way cross-over stud y. Eight healthy volunteers ingested daily 1500 mg erythromycin for 6 days, 100 mg fluvoxamine for 5 days (Days 2-6), both erythromycin and fluvoxamin e, or placebo. On Day 6, each subject received a single dose of 0.6 mg/kg r opivacaine IV over 30 min. Ropivacaine, 3-hydroxyropivacaine, and 2',6'-pip ecoloxylidide in venous plasma and urine samples were measured for up to 12 h and 24 h, respectively. Fluvoxamine increased the area under the drug pl asma concentration-time curve (AUC) of ropivacaine 3.7-fold (P < 0.001), pr olonged the elimination half-life (t(1/2)) from 2.3 to 7.4 h (P < 0.01), an d decreased the clearance by 77% (P < 0.001). Erythromycin alone had only a minor effect on the pharmacokinetics of ropivacaine. However, when compare d with fluvoxamine alone, the combination of fluvoxamine and erythromycin f urther increased the area under the drug plasma concentration-time curve an d t(1/2) of ropivacaine by 50% (P < 0.01). We conclude that inhibition of C YP1A2 by fluvoxamine considerably reduces elimination of ropivacaine. Conco mitant use of fluvoxamine and CYP3A4 inhibitor erythromycin further increas es plasma ropivacaine concentration by decreasing its clearance.