Drug metabolism and disposition : the biological fate of chemicals
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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 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.
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Drug Metab. Dispos. · Sep 1996
Human reductive halothane metabolism in vitro is catalyzed by cytochrome P450 2A6 and 3A4.
The anesthetic halothane undergoes extensive oxidative and reductive biotransformation, resulting in metabolites that cause hepatotoxicity. Halothane is reduced anaerobically by cytochrome P450 (P450) to the volatile metabolites 2-chloro-1,1-difluoroethene (CDE) and 2-chloro-1,1,1-trifluoroethane (CTE). The purpose of this investigation was to identify the human P450 isoform(s) responsible for reductive halothane metabolism. ⋯ The P450 2E1 inhibitors 4-methylpyrazole and diethyldithiocarbamate inhibited CDE and CTE formation by 20-45% and 40-50%, respectively; however, cDNA-expressed P450 2E1 did not catalyze significant amounts of CDE or CTE production, and microsomal metabolite formation was not correlated with P450 2E1 activity. This investigation demonstrated that human liver microsomal reductive halothane metabolism is catalyzed predominantly by P450 2A6 and 3A4. This isoform selectivity for anaerobic halothane metabolism contrasts with that for oxidative human halothane metabolism, which is catalyzed predominantly by P450 2E1.