1.[Structure and activity relationship of propafenone and alkylesters of 2-and 4-[(3-propylamino-2-hydroxy)-propoxy]-phenylcarbamic acid].
Garaj V1, Remko M. Ceska Slov Farm. 2002 May;51(3):145-9.
Conformation analysis was performed in propaphenone and two potential antiarrhythmic agents of the carbamate type, employing the method of molecular mechanics for calculations. Energetically stable conformers were optimized by means of the quantumchemical method AM1 and the optimized structures were used to construct the pharmacophore. Using the programme Chem-X, four groups of stable conformations of these drug were found, and comparisons by means of the molecular graphic method were employed to graphically visualize the degree of their similarity and to determine the interatomic distances of the groups with free electron pairs and a lipophilic aromatic nucleus.
2.Clinical pharmacokinetics of mexiletine.
Labbé L1, Turgeon J. Clin Pharmacokinet. 1999 Nov;37(5):361-84.
Mexiletine, a class Ib antiarrhythmic agent, is rapidly and completely absorbed following oral administration with a bioavailability of about 90%. Peak plasma concentrations following oral administration occur within 1 to 4 hours and a linear relationship between dose and plasma concentration is observed in the dose range of 100 to 600 mg. Mexiletine is weakly bound to plasma proteins (70%). Its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is eliminated slowly in humans (with an elimination half-life of 10 hours). It undergoes stereoselective disposition caused by extensive metabolism. Eleven metabolites of mexiletine are presently known, but none of these metabolites possesses any pharmacological activity. The major metabolites are hydroxymethyl-mexiletine, p-hydroxy-mexiletine, m-hydroxy-mexiletine and N-hydroxy-mexiletine. Formation of hydroxymethyl-mexiletine, p-hydroxy-mexiletine and m-hydroxy-mexiletine is genetically determined and cosegregates with polymorphic debrisoquine 4-hydroxylase [cytochrome P450 (CYP) 2D6] activity.
3.Metabolism of propafenone and verapamil by cryopreserved human, rat, mouse and dog hepatocytes: comparison with metabolism in vivo.
Reder-Hilz B1, Ullrich M, Ringel M, Hewitt N, Utesch D, Oesch F, Hengstler JG. Naunyn Schmiedebergs Arch Pharmacol. 2004 Apr;369(4):408-17. Epub 2004 Mar 4.
In the present study we examined the metabolism of [(14)C]propafenone (P) and [(14)C]verapamil (V) using cryopreserved human, dog (Beagle), rat (Sprague-Dawley) and mouse (NMRI) hepatocytes. The percentage ratios of the metabolites were identified after extraction by HPLC with UV and radioactivity detection. Phase-II metabolites were cleaved using beta-glucuronidase. Metabolism of the drugs by cryopreserved hepatocytes was compared with that in the respective species in vivo. All phase-I and -II metabolites known from in vivo experiments: 5-hydroxy-P (5-OH-P); 4'-hydroxy-P (4'-OH-P); N-despropyl-P (NdesP) and the respective glucuronides, were identified after incubation with cryopreserved hepatocytes. Interspecies differences were observed concerning the preferential position of propafenone hydroxylation: 5-OH-P made up 91, 51, 16 and 3% of the total metabolites after incubation with cryopreserved human ( n=4), dog ( n=3), rat ( n=3) and mouse ( n=4) hepatocytes respectively.
4.Validated capillary electrophoresis assay for the simultaneous enantioselective determination of propafenone and its major metabolites in biological samples.
Afshar M1, Thormann W. Electrophoresis. 2006 Apr;27(8):1517-25.
A robust, inexpensive, and fully validated CE method for the simultaneous determination of the enantiomers of propafenone (PPF), 5-hydroxy-propafenone (5OH-PPF) and N-despropyl-propafenone (NOR-PPF) in serum and in in vitro media is described. It is based upon liquid-liquid extraction at alkaline pH followed by analysis of the reconstituted extract by CE in presence of a pH 2.0 running buffer composed of 100 mM sodium phosphate, 19% methanol, and 0.6% highly sulfated beta-CD. For each compound, the S-enantiomers are shown to migrate ahead of their antipodes, and the overall run time is about 30 min. Enantiomer levels between 25 and 1000 ng/mL provide linear calibration graphs, and the LOD for all enantiomers is between 10 and 12 ng/mL. The assay is shown to be suitable for the determination of the enantiomers of PPF and its metabolites in in vitro incubations comprising human liver microsomes or single CYP450 enzymes (SUPERSOMES). Incubations with CYP2D6 SUPERSOMES revealed, for the first time, the simultaneous formation of the enantiomers of 5OH-PPF and NOR-PPF with that enzyme.