Metabolism and excretion of ropivacaine in humans

The pharmacokinetics, biotransformation, and urinary excretion of ropivacaine (Naropin), a new local anesthetic agent, have been studied in six healthy male volunteers after a 15-min iv infusion of 152 mumol (50 mg) of [14C]ropivacaine, with a specific radioactivity of 22.5 kBq/mumol (8.8 kBq/mg). Blood, urine, and feces were collected for up to 96 hr after administration. The plasma and urine samples were analyzed for unchanged ropivacaine and for four of its metabolites, i.e. 3-OH-2',6'-pipecoloxylidide (3-OH-PPX), 4-OH-ropivacaine, 3-OH-ropivacaine, and the N-dealkylated metabolite PPX, using GC and HPLC methods. The presence of 2,6-xylidine in plasma was also analyzed. The metabolites were quantified after acidic hydrolysis. The radioactivity could be followed in plasma for up to 14 hr after administration, with ropivacaine being the predominant compound in the early samples. The concentrations of the aforementioned metabolites in plasma were below or just above the lower limit of quantification, and no 2,6-xylidine was detected. The maximum plasma concentration of ropivacaine was 5.9 +/- 2.6 microM (1.6 +/- 0.7 mg/liter), with an elimination half-life of 2.0 +/- 0.3 hr and a total plasma clearance of 397 +/- 127 ml/min. The maximum plasma concentration value for the total radioactivity was 5.5 +/- 2.4 microM (1.5 +/- 0.7 mg/liter) and the elimination half-life was 5.4 +/- 2.9 hr. [14C]Ropivacaine and its metabolites were mainly excreted in the urine, with a total recovery of 86 +/- 3% in the urine and 9 +/- 1% in the feces after 96 hr. Most of the radioactivity (about 68%) was excreted within 12 hr. Ropivacaine was extensively metabolized, and only 1 +/- 0.6% of the dose was excreted unchanged in the urine. The major metabolite identified in the urine was conjugated 3-OH-ropivacaine, which was excreted to an extent of 37 +/- 3% of the dose. The urinary excretion of 4-OH-ropivacaine was < 1%, whereas the N-dealkylated metabolites PPX and 3-OH-PPX accounted for 2 and 3% of the dose, respectively. An additional hydroxylated metabolite, 2-OH-methyl-ropivacaine, was tentatively identified in the urine of some volunteers, accounting for about 4-15% of the dose.