Journal of
Analytical Toxicology, Vol.
27, November/December 2003
I
Case Report]
Fatal PropafenoneOverdoses: Case Reportsand A Review of the Literature Franck Clarot 1,*, Jean Pierre Goull~ 2, Marline Horst 1, Emmanuelle Vaz 1, Christian Lacroix z, and Bernard Proust 1 1Medical ForensicInstitute, Rouen University Hospital Charles Nicolle, Rouen, Franceand 2Pharmacokinetic and Toxicology Laboratory,Jacques Monod Hospital, 76083 Le Havre, France
[ Abstract ]
Case Histories
First synthesized in 1970, propafenone is a frequently used 1C antiarrhythmicdrug metabolized into two major metabolites, 5-hydroxypropafenone and norpropafenone. Paradoxically, fatal intoxication is rarely described, and only six caseshave been reported in the literature. We report our experience with two patients founddead of self-inflictedpoisoningwhere the propafenoneblood concentrationwas very high (one concentration to our knowledge is one of the highest reported in the literature). At autopsy, no evidence of significantpathological diseasewere found. Propafenonewasdetected in blood by gas chromatography-massspectrometryand by high-performance liquid chromatographyusinga diode.array detector, respectively, as propafenone artifact and propafenone. Blood propafenone concentrationswere 4180 ng/mL and 9123 ng/mL. The literature regarding propafenone pharmacokinetic and intoxication is reviewed, and we discussthe low death rate attributed to this drug in contrast to its frequent use.
Case report #1 A 46-year-old man was found dead in his residence. Several medications were found near the body, and there was no evidence of violence.
Introduction
Propafenone is a class 1C antiarrhytmic agent similar to fiecainide and encainide. Propafenone exhibits ~-adrenergic and calcium channel-blocking activities. It has been used extensively in Europe since 1977 for the treatment of supraventricular and ventricular arrhythmias. It has only been used in the United States since 1989 after Food and Drug Administration approval. Since 1990, propafenone use has been restricted to life-threatening ventricular arrhythmias because of increased mortality (1). Propafenone intoxication is rare, and only a limited number of cases of lethal self-poisoning have been reported in the literature.
9Author to whom correspondenceand reprint requestsshould be addressed: Dr. FranckClarot, Institut de Mc~decineLC~gale,CHU Rouen - Charles Nicolle, 76031 Rouencedex, France. E-mail:
[email protected].
Case report #2 A 43-year-oldman was found dead in his car after consuming excessive amounts of prescribed medication. Propafenone and clomipramine were found near the body. At autopsy, there was no evidence of a previous history of disease, and no significant pathological findings were discovered.
Experimental
Screening and quantitation procedure Comprehensivetoxicologicalanalysiswas performedon blood for case #1 and on blood and urine specimens for case #2. This included volatile blood and urine screening by headspace gas chromatography (GC-HS); qualitative barbiturates, tricyclic antidepressants, benzodiazepines, opiates, cocaine metabolite, sympathomimetic amines screening of blood and urine by fluorescence polarization immunoassay (FPIA); drug screening of the urine by FPIA for cannabinoids; quantitative acetaminophen and salicylatedetermination of blood and urine by FPIA; and digoxin determination of blood by FPIA. Blood carbon monoxide was evaluated by spectroscopy. Urine and blood were screened by ToxiLabATM and analyzed by gas chromatography-mass spectrometry (GC--MS).The extract was dissolved in methanol. The same blood extract was screened by liquid chromatography coupled with diode-array detection (HPLC-DAD). Instrumentation GC-MS analysis was performed using a Hewlett-Packard 5973 mass selective detector (Palo Alto, CA) interfaced with an HP 5890 GC with 7673 auto-injector and sample tray. Injections
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595
Journal of Analytical Toxicology, Vol. 27, November/December 2003
were made in the splitless mode on to an HP-5 MS column (30 m x 0.25-mm i.d., 0.25-mm film thickness, Hewlett-Packard). The initial column temperature was 40~ and was programmed to rise to 300~ at 20~ Injection and interface temperature were 260~ and 280~ respectively. Helium was used as a carrier gas. Data were acquired in a scan mode from m/z 40 to 500 amu. The HPLC-DAD (HP series 1050-I040M, series II detection system) was used under the following conditions: flow rate, 0.42 mL/min and acetonitrile concentration from 3% (v/v) to 70% (time 22 min) in the phosphate buffer (pH 3.2). Each extract was injected into a C~s BDS column (3 um x 100 x 3-mm i.d.) via an HP 1050 autosampler. Quantitation of propafenone and its metabolite norpropafenone was performed according to the following procedure: to 1 mL blood (in duplicate) were added 50 uL NH4Cl buffer (pH 9.2), 50 I~Lof prazepam (10 mg/L, internal standard), and 2 mL dichloromethane/hexane/ethylacetate (5:4:1, v/v). After agitation and centrifugation, the organic phase was removed and evaporated to dryness. The residue was reconstituted with 100 gL of mobile phase/methanol (50:50, v/v); 50 pL was injected into the HPLC column. The spectrophotometric detector was set at 250 nm.
dard. The standards and specimens were analyzed together. The ratios of the peak area from propafenone to that from internal standard, prazepam, were plotted versus the concentration of propafenone. The calibration curve was linear over the range of 1000 to 10,000 ng/mL. The least-squares analysis of the data had a correlation coefficient of 1.000. Quantitation of propafenone metabolite was performed and expressed as propafenone. Similarly, clomipramine and desmethylclomipramine standards of 100, 250, 500, and 1000 ng/mL were prepared by adding clomipramine and desmethylclomipramine to clomipramine-free blood, and a calibration curve was generated in the same manner as previously described. The curve was linear over the calibration range, and the correlation coefficient was 1.000 for both clomipramine and desmethylclomipramine.
Results and Discussion For both cases, the blood methanol extract was analyzed by ToxiLab and GC-MS. Only propafenone artifact was identified
Calibration and accuracy Propafenone standards were prepared at concentrations of 1000, 2500, 5000, and 10,000 ng/mL by adding propafenone to propafenone-free blood with prazepam as the internal stan-
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Table I. Blood ToxicologicalFindingsfor Both Cases
m/z
Figure 1. Mass spectrum comparison of case #2 extracted blood and Pfleger Maurer library (propafenone methanol artifact). Propafenone* Norpropafenone* Clomipramine* Norclomipramine* Ethanol*
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