N-Acetylprocainamide

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John Fawcett Wilson - One of the best experts on this subject based on the ideXlab platform.

  • acecainide n acetylprocainamide
    1995
    Co-Authors: John Fawcett Wilson
    Abstract:

    The drug acecainide or N-Acetylprocainamide is also the principal active metabolite of the class la anti-arrhythmic procainamide. It has less pharmacological activity, a longer duration of action, and produces less frequent cardiac complications and hypersensitivity reactions than procainamide. The acetylation of procainamide is subject to genetic polymorphism with 30-40% being converted in fast acetylators. Up to 85% of a dose of acecainide is excreted unchanged in urine. The half-life in plasma is 6-9 hours (procainamide 2.5-4 hours), increasing with renal impairment. Therapeutic concentrations in plasma have been proposed to be 10-30 μg/ ml for the sum of both procainamide and acecainide, or 4-10 μg/ml for procainamide and 6-20 μg/ml for acecainide.

Ronald P Mason - One of the best experts on this subject based on the ideXlab platform.

  • procainamide but not n acetylprocainamide induces protein free radical formation on myeloperoxidase a potential mechanism of agranulocytosis
    Chemical Research in Toxicology, 2008
    Co-Authors: Arno G Siraki, Leesa J Deterding, Marcelo G Bonini, Jinjie Jiang, Marilyn Ehrenshaft, Kenneth B Tomer, Ronald P Mason
    Abstract:

    Procainamide (PA) is a drug that is used to treat tachycardia in postoperative patients or for long-term maintenance of cardiac arrythmias. Unfortunately, its use has also been associated with agranulocytosis. Here, we have investigated the metabolism of PA by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that PA oxidation by MPO/H2O2 would produce a PA cation radical that, in the absence of a biochemical reductant, would lead to the free radical oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms by the reaction of DMPO with a protein free radical. We found that PA metabolism by MPO/H2O2 induced the formation of DMPO−MPO, which was inhibited by MPO inhibitors and ascorbate. N-acetyl-PA did not cause DMPO−MPO formation, indicating that the unsubstituted aromatic amine was more oxidizable. PA had a lower calculated ionization potential than N-acetyl-PA. The DMPO adducts ...

Arno G Siraki - One of the best experts on this subject based on the ideXlab platform.

  • procainamide but not n acetylprocainamide induces protein free radical formation on myeloperoxidase a potential mechanism of agranulocytosis
    Chemical Research in Toxicology, 2008
    Co-Authors: Arno G Siraki, Leesa J Deterding, Marcelo G Bonini, Jinjie Jiang, Marilyn Ehrenshaft, Kenneth B Tomer, Ronald P Mason
    Abstract:

    Procainamide (PA) is a drug that is used to treat tachycardia in postoperative patients or for long-term maintenance of cardiac arrythmias. Unfortunately, its use has also been associated with agranulocytosis. Here, we have investigated the metabolism of PA by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that PA oxidation by MPO/H2O2 would produce a PA cation radical that, in the absence of a biochemical reductant, would lead to the free radical oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms by the reaction of DMPO with a protein free radical. We found that PA metabolism by MPO/H2O2 induced the formation of DMPO−MPO, which was inhibited by MPO inhibitors and ascorbate. N-acetyl-PA did not cause DMPO−MPO formation, indicating that the unsubstituted aromatic amine was more oxidizable. PA had a lower calculated ionization potential than N-acetyl-PA. The DMPO adducts ...

Han-joo Maeng - One of the best experts on this subject based on the ideXlab platform.

  • Physiologically-Based Pharmacokinetic Modeling for Drug-Drug Interactions of Procainamide and N-Acetylprocainamide with Cimetidine, an Inhibitor of rOCT2 and rMATE1, in Rats
    MDPI AG, 2019
    Co-Authors: Yoo-seong Jeong, Anusha Balla, Kwang-hoon Chun, Suk-jae Chung, Han-joo Maeng
    Abstract:

    Previous observations demonstrated that cimetidine decreased the clearance of procainamide (PA) and/or N-Acetylprocainamide (NAPA; the primary metabolite of PA) resulting in the increased systemic exposure and the decrease of urinary excretion. Despite an abundance of in vitro and in vivo data regarding pharmacokinetic interactions between PA/NAPA and cimetidine, however, a mechanistic approach to elucidate these interactions has not been reported yet. The primary objective of this study was to construct a physiological model that describes pharmacokinetic interactions between PA/NAPA and cimetidine, an inhibitor of rat organic cation transporter 2 (rOCT2) and rat multidrug and toxin extrusion proteins (rMATE1), by performing extensive in vivo and in vitro pharmacokinetic studies for PA and NAPA performed in the absence or presence of cimetidine in rats. When a single intravenous injection of PA HCl (10 mg/kg) was administered to rats, co-administration of cimetidine (100 mg/kg) significantly increased systemic exposure and decreased the systemic (CL) and renal (CLR) clearance of PA, and reduced its tissue distribution. Similarly, cimetidine significantly decreased the CLR of NAPA formed by the metabolism of PA and increased the AUC of NAPA. Considering that these drugs could share similar renal secretory pathways (e.g., via rOCT2 and rMATE1), a physiologically-based pharmacokinetic (PBPK) model incorporating semi-mechanistic kidney compartments was devised to predict drug-drug interactions (DDIs). Using our proposed PBPK model, DDIs between PA/NAPA and cimetidine were successfully predicted for the plasma concentrations and urinary excretion profiles of PA and NAPA observed in rats. Moreover, sensitivity analyses of the pharmacokinetics of PA and NAPA showed the inhibitory effects of cimetidine via rMATE1 were probably important for the renal elimination of PA and NAPA in rats. The proposed PBPK model may be useful for understanding the mechanisms of interactions between PA/NAPA and cimetidine in vivo

Jinjie Jiang - One of the best experts on this subject based on the ideXlab platform.

  • procainamide but not n acetylprocainamide induces protein free radical formation on myeloperoxidase a potential mechanism of agranulocytosis
    Chemical Research in Toxicology, 2008
    Co-Authors: Arno G Siraki, Leesa J Deterding, Marcelo G Bonini, Jinjie Jiang, Marilyn Ehrenshaft, Kenneth B Tomer, Ronald P Mason
    Abstract:

    Procainamide (PA) is a drug that is used to treat tachycardia in postoperative patients or for long-term maintenance of cardiac arrythmias. Unfortunately, its use has also been associated with agranulocytosis. Here, we have investigated the metabolism of PA by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that PA oxidation by MPO/H2O2 would produce a PA cation radical that, in the absence of a biochemical reductant, would lead to the free radical oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms by the reaction of DMPO with a protein free radical. We found that PA metabolism by MPO/H2O2 induced the formation of DMPO−MPO, which was inhibited by MPO inhibitors and ascorbate. N-acetyl-PA did not cause DMPO−MPO formation, indicating that the unsubstituted aromatic amine was more oxidizable. PA had a lower calculated ionization potential than N-acetyl-PA. The DMPO adducts ...