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.
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Drug Metab. Dispos. · Apr 1996
Comparative StudyWarfarin-fluconazole. III. A rational approach to management of a metabolically based drug interaction.
The results of studies of the effect of fluconazole on cytochrome P450 (P450) 2C9 activity in vivo and in vitro are used to develop an approach to the safe management of the warfarin-fluconazole drug interaction. This approach begins with a determination of an in vitro Ki value (22 microM), which may be used to relate fluconazole plasma concentrations to inhibitory effect on P4502C9 activity and (S)-warfarin half-life. ⋯ The effect of interindividual pharmacokinetic variability on outcome quality is explored in simulation studies that indicate that a stepped-dose reduction schedule will be superior to a one-time dose reduction. The in vivo K, was found to predict accurately the magnitude of the fluconazole interaction study with another P4502C9 substrate tolbutamide.
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Drug Metab. Dispos. · Mar 1996
Dose-related distribution of codeine and its metabolites into rat hair.
Drugs and endogenous compounds may be incorporated into the matrix of a growing hair shaft. However, the relationship between incorporation and dose or time course of plasma concentrations is poorly defined. The purpose of this study was to compare plasma and hair concentrations of codeine and its metabolites after various doses of codeine. ⋯ Codeine and morphine are incorporated into rat hair in a dose-proportional fashion. Morphine glucuronide can be found in rat hair after codeine administration. The codeine concentration in hair is the same whether the drug is administered by constant intravenous infusion or daily intraperitoneal injections if the areas under the plasma concentration vs. time curve values are considered.
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Drug Metab. Dispos. · Feb 1996
Absorption, distribution, metabolism, and excretion of N,N-diethyl-M-toluamide in the rat.
This study was conducted to evaluate the pharmacokinetic parameters of absorption, distribution, metabolism, and excretion (ADME) of the personal insect repellent N,N-diethyl-m-toluamide (DEET) after oral or dermal administration of [14C]DEET in the rat. Six experiments were conducted using separate groups, each consisting of five male and five female rats. Three experiments involved the determination of ADME patterns after oral administration of [14C]DEET as: 1) a single low dose (100 mg DEET/kg body weight); 2) a single high dose (500 mg DEET/kg body weight); and 3) a repeated low dose (100 mg DEET/kg body weight daily for 14 days). ⋯ Two major urinary metabolites were identified by mass spectroscopy. In both metabolites, the aromatic methyl substituent in the DEET molecule was oxidized to a carboxylic acid moiety. One of the metabolites also had undergone N-dealkylation of an ethyl substituent on the amide moiety.