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5 Hydroxypropafenone

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J Seshagiri V L N Rao – One of the best experts on this subject based on the ideXlab platform.

  • highly sensitive uhplc ms ms method for the simultaneous estimation of propafenone and its metabolites 5 Hydroxypropafenone and n depropylpropafenone on human dried blood spots technique and application to a pharmacokinetic study
    Journal of Pharmaceutical and Biomedical Analysis, 2017
    Co-Authors: Adinarayana Andy, Raja Reddy Kallem, Ramesh Mullangi, Divya Andy, J Seshagiri V L N Rao

    Abstract:

    A highly sensitive, rapid and selective UHPLC-MS/MS method has been developed and validated for quantification of the propafenone (PF), 5Hydroxypropafenone (5-OHPF) and N-depropylpropafenone (N-DPF) on human dried blood spot (DBS). The assay procedure involves a solid-liquid extraction of PF, 5-OHPF and N-DPF and amlodipine (internal standard, I.S.) from dried human DBS cards using water and acetonitrile. The chromatographic resolution was achieved on a BEH C18 column using a gradient mobile phase consisting of 0.1% formic acid in water and acetonitrile with 0.1% formic acid at flow rate of 0.6mL/min. The UHPLC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Total run time of analysis was 1.1min and elution of PF, 5-OHPF, N-DPF and I.S. occurred at 0.69, 0.6, 0.68 and 0.73min, respectively. A detailed method validation was performed as per the regulatory guidelines and the standard curves found to be linear in the range of 5.11-1000ng/mL for PF and 5-OHPF and 0.51-100ng/mL for N-DPF with a correlation coefficient of ≥0.99 for all the drugs. The intra- and inter-day accuracies were in the range of 95.6-107 and 93.5-103; 93.4-106 and 96.3-107 and 87.9-103 and 96.5-102%, for PF, 5-OHPF and N-DPF, respectively. The intra- and inter-day precisions were in the range of 2.50-5.52 and 3.38-5.18; 2.16-6.34 and 3.23-4.94 and 2.63-7.55 and 1.56-10.2%, for PF, 5-OHPF and N-DPF, respectively. The validated assay method was successfully applied to a pharmacokinetic study in humans. The key pharmacokinetic parameters AUC0-∞ and Cmax were 6057±1526, 2002±515 and 525±202 ng*h/mL and 653±183, 295±37.5 and 68.4±13.6ng/mL for PF, 5-OHPF and N-DPF, respectively.

Paul I. Dargan – One of the best experts on this subject based on the ideXlab platform.

  • Propafenone poisoning: a case report with plasma propafenone concentrations
    Journal of Medical Toxicology, 2010
    Co-Authors: Hanna Ovaska, Andrew Ludman, Edgar P. Spencer, David M. Wood, Alison L. Jones, Paul I. Dargan

    Abstract:

    Propafenone is an anti-arrhythmic drug used in the management of supraventricular and ventricular arrhythmias. It is metabolised through cytochrome P450 2D6 pathways; the major metabolites possess anti-arrhythmic activity. The cytochrome P450 CYP2D6 is coded by more than 70 alleles resulting in great genetic polymorphism of CYP2D6 isoenzymes, and up to 7% of Caucasian population are poor metabolisers. This case report describes a patient with severe overdose of propafenone who presented with coma, seizures and cardiotoxicity. The patient was managed with intravenous glucagon, hypertonic sodium bicarbonate, hypertonic saline and inotropic support. The propafenone and its 5Hydroxypropafenone (5-OHP) metabolite were measured by high-performance liquid chromatography with ultraviolet detection (no assay was available at the time to measure N-despropyl propafenone concentrations). Toxicological screen showed propafenone concentrations at a maximum of 1.26 mg/L at 9-10 h post-presentation, falling to 0.25 mg/L at 27-28 h post-presentation. No propafenone metabolite 5-OHP was detected in any sample analysed. No antidepressant or analgesic drugs were detected in toxicological screen. Propafenone overdose has been reported to be associated with features of severe cardiovascular and CNS toxicity. Aggressive treatment, meticulous monitoring and supportive care was associated with a good outcome in this case.

  • Propafenone Poisoning—A Case Report with Plasma Propafenone Concentrations
    Journal of Medical Toxicology, 2010
    Co-Authors: Hanna Ovaska, Andrew Ludman, Edgar P. Spencer, David M. Wood, Alison L. Jones, Paul I. Dargan

    Abstract:

    Propafenone is an anti-arrhythmic drug used in the management of supraventricular and ventricular arrhythmias. It is metabolised through cytochrome P450 2D6 pathways; the major metabolites possess anti-arrhythmic activity. The cytochrome P450 CYP2D6 is coded by more than 70 alleles resulting in great genetic polymorphism of CYP2D6 isoenzymes, and up to 7% of Caucasian population are poor metabolisers. This case report describes a patient with severe overdose of propafenone who presented with coma, seizures and cardiotoxicity. The patient was managed with intravenous glucagon, hypertonic sodium bicarbonate, hypertonic saline and inotropic support. The propafenone and its 5Hydroxypropafenone (5-OHP) metabolite were measured by high-performance liquid chromatography with ultraviolet detection (no assay was available at the time to measure N -despropyl propafenone concentrations). Toxicological screen showed propafenone concentrations at a maximum of 1.26 mg/L at 9–10 h post-presentation, falling to 0.25 mg/L at 27–28 h post-presentation. No propafenone metabolite 5-OHP was detected in any sample analysed. No antidepressant or analgesic drugs were detected in toxicological screen. Propafenone overdose has been reported to be associated with features of severe cardiovascular and CNS toxicity. Aggressive treatment, meticulous monitoring and supportive care was associated with a good outcome in this case.

J. Evers – One of the best experts on this subject based on the ideXlab platform.

  • Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its Phase I and Phase II metabolites
    European Journal of Clinical Pharmacology, 1995
    Co-Authors: M. F. Fromm, S. Botsch, G. Heinkele, H. K. Kroemer, J. Evers

    Abstract:

    The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure. No difference was found in the plasma concentrations of propafenone and 5Hydroxypropafenone between the three groups. The propafenone glucuronide (PPFG) concentration was elevated in the older compared to the younger subjects (S-PPFG: 544 vs. 222 nmol · ml^−1 · mol^−1; R-PPFG: 576 vs. 304 nmol · ml^−1 · mol^−1). Although Glomerular filtration rate did not differ, the renal clearance of propafenone glucuronides was reduced in the former group, which could be attributed to their impaired renal secretion. A dramatic increase in propafenone glucuronide concentration was observed in the patients with renal failure (S-PPFG: 2783 nmol · ml^−1 · mol^−1; R-PPFG: 7340 nmol · ml^−1 · mol^−1). In summary, the disposition of propafenone and of its active metabolite 5Hydroxypropafenone was not affected by kidney dysfunction, indicating that no dose adjustment is necessary in patients with renal failure. The accumulation of drug glucuronides in older patients with apparently normal kidney function should be taken into account as a possible factor modifying drug therapy.