Effects of drug interactions and liver disease on the pharmacokinetics of ropivacaine

Background. Ropivacaine, a long-acting, enantiomerically pure amide-type local anesthetic, undergoes extensive hepatic metabolism in humans, with about 1% of an intravenous dose excreted unchanged in the urine. It is metabolized to 3-OHropivacaine by CYP1A2, and to PPX by CYP3A4. The aims of the present studies were to investigate (1) the effects of inhibition (with fluvoxamine, ciprofloxacin, erythromycin, clarithromycin, itraconazole, and oral contraceptives) and induction (with cigarette smoking and rifampicin) of CYP1A2 and CYP3A4, and (2) the effect of chronic end-stage liver disease on the pharmacokinetics of ropivacaine. Methods. A total of 44 (26 female and 18 male) healthy volunteers participated in Studies I to V, and 13 (7 female and 6 male) patients with chronic end-stage liver disease in Study V. The first four studies were placebo-controlled, randomized, double-blind, and cross-over in design, to assess the effects of clarithromycin, itraconazole, erythromycin, fluvoxamine, and rifampicin on the pharmacokinetics of ropivacaine. The effect of oral contraceptives was evaluated in the combined placebo phases of these four studies. Study III was also designed to compare the pharmacokinetics of ropivacaine in smokers and nonsmokers. Study V was an open parallel group study to assess the effect on the pharmacokinetics of ropivacaine of chronic end-stage liver disease. After the pretreatments with these inhibitors or inducers in Studies I to IV, and without any pretreatment in Study V, each subject received an intravenous infusion of 0.6 mg/ kg ropivacaine hydrochloride during a period of 30 minutes. Ropivacaine, 3-OHropivacaine, and PPX in venous plasma and in urine samples were measured for up to 12 and 24 hours, respectively. Results. Fluvoxamine reduced the ropivacaine clearance by 77% and ciprofloxacin by 31%. Itraconazole, erythromycin, and clarithromycin reduced the clearance only insignificantly, but a combination of fluvoxamine and erythromycin reduced it by 86%. Fluvoxamine and ciprofloxacin raised the excretion of PPX in urine, and reduced the urinary excretion of 3-OHropivacaine. Itraconazole reduced the excretion of PPX in urine, and erythromycin raised the urinary excretion of 3-OHropivacaine. Oral contraceptives reduced the ropivacaine clearance by 49%, elevated PPX excretion, and reduced the 3-OHropivacaine excretion. Chronic end-stage liver disease reduced the ropivacaine clearance by 60% and reduced the urinary excretion of 3-OH-ropivacaine, without affecting the PPX excretion. Fluvoxamine, combined fluvoxamine and erythromycin, and chronic end-stage liver disease caused an increase in the fraction excreted in urine as unchanged ropivacaine. Conclusions. The results of the present studies demonstrate the principal role of hepatic CYP1A2, and suggest the modest role of CYP3A4, in the elimination of ropivacaine in humans in vivo. The combination of fluvoxamine and erythromycin reduced ropivacaine clearance by 86%, implying ropivacaine plasma concentrations about 7-fold higher at steady-state during continuous ropivacaine infusion. When continuous infusion or multiple injections of ropivacaine are given, clinicians should be aware of increased plasma concentrations in patients taking potent CYP1A2 inhibitors, or a combination of CYP1A2 and CYP3A4 inhibitors, as well as in patients with chronic end-stage liver disease.