Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers

AIM: To study the influence of inducers of drug metabolism enzyme, β-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes.METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots.Propafenone enantiomer concentrations were assayed by a chiral HPLC.RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubstion of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R ( - ) isomer was observed in metabolism st Iow substrate concentrations of racemic propafenone, but lost the stereoselectivity st high substrate concentrations.However; in control group, no stereeselectivity was observed. The enzyme kinetic parameters were: ① Km.Control group: R( - ) 83 ± 6, S( + ) 94 ± 7; BNF group: R (-)105 ± 6, S( + )128 ± 14; DEX group: R( - ) 86± 11, S( + ) 118 ± 16; ② vmax. Control group: R( - ) 0.75 ± 0.16, S( + ) 0.72±0.07; BNF group: R( - )1.04± 0.15, S( + )1.07±14; DEX group: R( - ) 0.93 ± 0.06, S( + ) 1.04 ± 0.09; (③)Clint. Control group: R( - ) 8.9± 1.1, S( + ) 7.6±0.7; BNFgroup: R( - )9.9±0.9, S( + )8.3±0.7; DEX group: R( - )10.9± 0.8, S( + ) 8.9 ± 0.9. The enantiomeric differences in Km and Clint were both significant, but not in Vmax, in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group.Furthermore, Km and Umax were both significantly less than those in BNF or DEX group. In the rat liver microsorne induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at Iow substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereo.selective with R ( - )-isomer being impaired more than S ( + )-isomer. The inhibition constant (Ki) of S ( + )- and R ( - )-propafenone, calculated from Dixon plots, was 15.4 and 8.6 mg.L-1, respectively.CONCLUSION: CYP1A subfamily (induced by BNF) and CYP3A4(induced by DEX) have pronounced contribution to propafenone N-deselkylation which exhibited stereoselectivity depending on substrate concentration. The molecular base for this phenomenon is the stereoselectivity in affinity of subetrate to the enzyme activity centers instead of at the catalyzing sites.

Selective killing effect of oxytetracycline,propafenone and metamizole on A549 or Hela cells

Objective： To determine the selective killing effect of oxytetracycline, propafenone and metamizole on A549 or Hela cells. Methods： Proliferation assay, lactate dehydrogenase （LDH） assay, apoptosis detecting, flow cytometry and western blot were performed. Results： It was found that treatment with propafenone at the concentration of 0.014 g/L or higher for 48 h could induce apoptosis in Hela cells greatly, while it was not observed in oxytetracycline and metamizole at the concentration of 0.20 g/L for 48 h. Oxytetracycline, propafenone and metamizole all displayed evident inhibitory effects on the proliferation of A549 cells. The results of LDH assay demonstrated that the drugs at the test range of concentration did not cause necrosis in the cells. Propafenone could elevate the protein level of P53 effectively （P〈0.01）. Conclusions： Oxytetracycline, propafenone and metamizol （dipyrone） all displayed evident inhibitory effects on the proliferation of A549 cells. Propafenone also displayed evident inhibitory effects on the proliferation of Hela cells.

Electrophysiologic Effects of Propafenone on Action Potential of Neonatal and Adult Purkinje Fibers

The electrophysiological effects of 5.8×10-6 mol/L propafenonewere studied in neonatal canine Purkinje fiber compared with changes in theadult canine. The method used was microelectrode technique. This study sug-gests that Purkinje fibers are less sensitive to propafenone in the neonate than inthe adult, but at shorter ample lengths, the difference between them is not sig-nificant.

Effects of Isoproterenol and Metoprolol on the Suppression of Propafenone on with Supraventricular Tachycardia

This study was to determine whether isoproterenol (Iso) reverses the effects of propafenone(Pro) on the induction of supraventricular tarhycardia and whether the revergal during electrophysiologicstudy (EPS) is predictive of clinical recurrences of SVT during long-term treatment with Pro.Thirtypatients with inducible sustained SVT at baseline state were studied. Iso infusion at a rate necessary toachieve a 20%-40% increase in heart rate completely (16/28 cases,57%) or partially (5/28 case, 18%)revereed Pro's suppressant effects on the induction of SVT.There were clinical recurrcnces of SVT in fiveof 16 patients (31%) treated on a long-term basis (mean 4.5±3.6 months) with Pro,Iso completelyreveroed Pro's supprosant effect on the induction of SVT in four of these five patients (80%).These fivepatients then were treated with Pro and metoprolol and no further clincal recnrrences of SVT.These resultssuggested that reveroal by Iso ofpro's suppresaant effects on the induction of SVT may identify patients whoare likely to experience clinical recurrence of SVT and these patients may benefit from treatment with aB-blocker during longterm therapy with Pro.

Electrophysiologic Effects of Propafenone on Ischemic Ventricular Tachyarrhythmias

Objectives To observe the electrophysiologic effects of propafenone （Prop） on ischemic ventricular tachyarrhythmias. Methods A canine ischemic ventricular tachyarrhythmia model was established in open-chest dogs subjected to programmed electrical stimulation （PES） on 5-8 days after acute myocardial infarction. The electrophysiologic effects of propafenone were observed in the model. Results Propafenone distinctly lengthened the QTc interval （P 〉 0.01） and effective refractory period （ERP） of normal and ischemic ventricular myocardium （NERP and IERP） respectively （P 〉 0.01）, decreased the dispersion of ERP in ischemic myocardium and in left ventricle （P 〉 0.01）, and increased the diastolic excitability threshold of normal and ischemic ventricular myoeardium remarkably （P 〉 0.01）. Propafenone effectively prevented PES-induced ventricular tachycardia （VT） or ventricular fibrillation （VF） （P 〉 0.01） and ischemia-induced VT/VF （P 〉 0.05）. Conclusions The results indicated that the canine model produced by our methods is a worthy and reliable one, propafenone may be effective in preventing the onset of VT / VF after myocardial ischemic damage in dogs, and deserve further attention as an antifibrillatory agent.

Pharmacokinetics of propafenone hydrochloride sustained-release capsules in male beagle dogs

This paper describes the development and validation of a liquid chromatography–mass spectrometric assay for propafenone and its application to a pharmacokinetic study of propafenone administered as a new propafenone hydrochloride sustained-release capsule(SR-test), as an instant-release tablet(IR-reference) and as the market leader sustained-release capsule(Rythmol, SR-reference) in male beagle dogs(n ? 8). In Study A comparing SR-test with IR-reference in a crossover design T_(max) and t_(1/2) of propafenone for SR-test were significantly higher than those for IR-reference while C_(max) and AUC were lower demonstrating the sustained release properties of the new formulation. In Study B comparing SRtest with SR-reference the observed C_(max) and AUC of propafenone for SR-test(124.57140.0 ng/m L and612.07699.2 ng·h/m L, respectively) were higher than for SR-reference(78.52772.92 ng/m L and423.67431.6 ng·h/m L, respectively) although the differences were not significant. Overall, the new formulation has as good if not better sustained release characteristics to the market leader formulation.

体内普罗帕酮及其代谢物的GC-MS检验

In this paper,propafenone in judicial anatomy was quantitated and found to be 11.6 μg/mL in blood,17.8 μg/mL in urine,292 μg/g in gastric content and 196 μg/g in liver with GC-MS. Two metabolites from propafenone have been defined.In conclusion,as the dead body himself is a drug abuser and also his blood concentration of propafenone exceed the fatal dose,this case is finally identified to a death cause from the overdose of propanenone abuse.

CLINICAL OBSERVATION ON 84 CASES OF VENTRICULAR PREMATURE BEAT WITH DEFICIENCY SYNDROME TREATED BY QI LU TANG

From August 1989 to May 1994, 84 cases of ventricular premature beat (VPB) with deficiency syndrome were treated with our empirical prescription called Qi LU Tang (齐律汤 Decoction for Improving Abnormal Heart Beat). The total effective rate was 88.10%, being significantly different from that of the control group treated with the Western drug propafenone (P【 0.01). Qi Lu Tang exhibited a better therapeutic effect in cases of VPB with deficiency of qi. deficiency of both qi and blood, and deficiency of both qi and yin.