Journal of Analytical Toxicology, Vol. 25, October 2001 Case Report[ Citalopram Distribution in Postmortem Cases Barry Levine*, Xiang Zhang, and John E. Smialek Office of the Chief Medical Examiner, Stateof Maryland, 111 Penn Street, Baltimore, Maryland Gary W. Kunsman and Michael E. Fronlz Bexar County Medical Examiner's Office, 7337 Louis PasteurDrive, San Antonio, Texas78229 Downloaded from https://academic.oup.com/jat/article/25/7/641/729633 by guest on 27 September 2021 Abstract I N-desmethylcitalopram, N-didesmethylcitalopram, citalopram N-oxide, and a propionic acid metabolite. Only parent drug and This is a report of the analytical findings in 13 cases investigated by the desmethyl metabolite appear in the urine in amounts greater either the Office of the Chief Medical Examiner, State of Maryland than 10% of a dose (4). Steady-state plasma therapeutic concen- or the Bexar County (San Antonio, TX) Medical Examiner's Office trations of citalopram are in the range of 0.04 to 0.1 mg/L (5,6). in which citalopram, a highly selective serotonin reuptake inhibitor Although citalopram has been available in Europe as an anti- used therapeutically as an antidepressant, was identified. In 8 of depressant since the 1980s, the drug has only recently been the 9 cases in which both blood and urine specimens were approved for use in the United States. The following is a summary received, the urine citalopram concentration exceeded the blood of the analytical findings in cases reported to the Office of the concentration, indicating that urine is an appropriate specimen for Chief Medical Examiner, State of Maryland and the Bexar County screening citalopram use. The average liver to blood citalopram Medical Examiner's Office in which citalopram was identified. concentration ratio was 6.5 (range 3.1-13, n = 6). Three cases had blood concentrations less than 0.24 rag/L, which is in the reported antemortem therapeutic range of the drug. Eleven cases had blood concentrations less than 1.3 rag/L; in each of these cases, Experimental citalopram was determined to be an incidental finding to the ultimate cause of death. Quantitation of citalopram and the Citalopram and desmethylcitalopram extraction metabolite desmethylcitalopram in these cases yielded an average Citalopram and desmethylcitalopram standards were obtained parent-to-metabolite ratio of 6.4. from Forest Pharmaceuticals. A standard alkaline extraction pro- cedure was used to separate drug and metabolite from the biolog- ical matrix (7). Either ethylmorphine (cases 1-7) or methapyrilene Introduction (cases 8-13) was used as the internal standard. Quantitation was based on the area ratio of analyte to the internal standard in com- Citalopram is a bicyclic phthalane derivative with the chemical parison to four or five fortified blood or tissue calibrators at con- name (+)-l-(3-dimethylaminopropyl)- 1-(4-fluorophenyl)- 1,3- centrations ranging from 0.14 to 13.6 mg/L. Appropriate dilution dihydroisobenzofuran-5-carbonitrile. It is used therapeutically of specimens with distilled water was performed to ensure quanti- as an antidepressant, but is chemically unrelated to the tficyclic tation within the limits of the standard curve. antidepressants, tetracyclic antidepressants, or the selective serotonin reuptake inhibitors. It is available as the hydrobromide Instrumentation salt in tablets containing 20 or 40 mg as the free base. Citalopram and metabolite analysis (cases 1-7) were per- Citalopram is a highly selective serotonin reuptake inhibitor formed on a Hewlett-Packard 5890 gas chromatograph with a with little or no affinity for serotonin, dopamine, adrenergic, his- nitrogen-phosphorus detector (GC-NPD). The column used was tamine, GAB& muscarinic, or benzodiazepine receptors. The a cross-linked HP-5 fused silica capillary column (25 m x 0.32 drug exists as a racemic mixture; the (S)-enantiomer is associ- mm i.d. x 0.17-pro film thickness). Helium was the carrier gas ated with inhibition of serotonin reuptake (1). flowing at I mL/min. The oven temperature began at 100~ for After a 40-rag dose, the peak blood concentration occurs in 1 rain, increased at 30~ to 200~ increased at 10~ to about 4 h. The oral bioavailabilty is approximately 80% (2). The 260~ and increased at 20~ to 300~ holding for 8 rain. volume of distribution is 12 L/kg, and the drug is 80% plasma Splitless injection mode was utilized. protein bound. Hepatic metabolism occurs primarily through Citalopram and metabolite analysis (cases 8-13) were per- CYP3A4 and CYP2C19 (3). Metabolic products include formed on a Hewlett-Packard 6890 gas chromatograph with a flame-ionization detector (GC-FID). The column used was a * Author to whom correspondenceshould be addressed. cross-linked HP-1 fused-silica capillary column (12.5 m x 0.2- Reproduction (photocopying)of editorial content of this journal is prohibited without publisher's permission. 641 Journal of Analytical Toxicology, Vol. 25, October 2001 mm i.d. x 0.33-1Jm film thickness). Helium was the carrier gas methanol, ethanol, acetone, and isopropanol by headspace GC or flowing at 1 mL/min. The oven temperature began at 125~ and direct-injection capillary chromatography, acid/neutral drug increased at 20~ to 300~ holding for 6.25 rain. Three testing by GC-NPD or GC-FID, alkaline drug testing by microliters of the final extract was injected on column in the GC-NPD or GC-FID, and morphine by immunoassay. Table I split injection mode using a 30:1 split ratio. lists the drugs identified and quantitated in the blood of each Drug confirmation was performed using a Hewlett-Packard case. Also included in Table I are the final case dispositions. Table 5890 series 2 GC equipped with a 5972 mass selective detector. II provides the distribution of citalopram and desmethylcitalo- Similar chromatographic conditions as listed above were used. pram in all of the specimens received with each case. The mass spectrometer was operated in the full scan electron ionization mode. Discussion and Conclusions Results Despite the presence of a cyano group, citalopram displayed Downloaded from https://academic.oup.com/jat/article/25/7/641/729633 by guest on 27 September 2021 Specimens from each case were tested for volatiles and thera- good analytical characteristics using GC. The presence of two peutic and abused drugs. This included volatile testing for nitrogen atoms makes the parent and metabolite amenable to detection with an NPD. In addition, the pres- Table I. Toxicology Results and Final Case Dispositions of the Presented Cases ence of both a cyano group and a fluorine atom would permit use of an electron capture Case BAC* Blood Dru8 Results Cause of Mannerof detector. Citalopram elutes from a DB-1 or a no. (g/dL) Drug Conc. (rag/L) death death DB-5 capillary column around clomipramine; this elution occurs after some serotonin reup- I neg citalopram 0.62 cardiac arrhythmia natural take inhibitors like fluoxetine and sertraline, pseudoephedrine 3.7 but prior to paroxetine. The desmethyl diphenhydramine 0.05 metabolite elutes after the parent drug, dif- 2 0.24 citalopram 0.95 multiple injuries accident fering from fluoxetine and sertraline where cyclobenzaprine 0.07 the desmethyl metabolite precedes the parent 3 neg citalopram 0.12 narcoticintoxication undetermined drug. free morphine 0.16 4 0.07 citalopram 1.3 gunshotwound suicide Blood and urine specimens were collected carbamazepine 8.9 in nine cases. In eight of these cases, the urine nordiazepam 0.1 citalopram concentration was greater than 5 neg citalopram 0.44 pulmonaryembolism natural the blood concentration. This indicates that lidocaine 5.5 urine is an appropriate specimen for screening diazepam 0.2 citalopram use. This is similar to tricyclic 6 neg citalopram 0.1 gunshotwound suicide antidepressants, tetracyclic antidepressants, orphenadrine 0.05 and selective serotonin reuptake inhibitors 7 neg citalopram 0.44 meperidineintoxication undetermined with the notable exception of sertraline, which meperidine 1.9 is present in very low concentrations in the normeperidine 0.9 promethazine 0.09 urine following therapeutic use. 8 neg citalopram 0.36 mixeddrug intoxication suicide In seven cases, both liver and kidney speci- secobarbital 40 mens were analyzed. The average liver to tramadol 0.12 blood ratio was 6.5 with a range of 3.1 to 13 9 neg citalopram 4.7 bupropionintoxication suicide (n = 6). A high liver-to-blood ratio is also bupropion 14 observed with other antidepressants. Possible I0 t 0.09 citalopram 0.11 GI hemorrhage natural sequestration of drug in the liver is also con- promethazine 0.15 sistent with the high volume of distribution hydrocodone 0.19 (12 L/kg) of the drug. The average kidney-to- 11 neg citalopram 0.09 ASCVD natural blood ratio was 3.0 with a range of ]..8 to 4..8 methadone 0.7 (n = 6). alprazolam 0.15 desa]kylfiurazepam 0.11 Heart and peripheral blood specimens were 12 neg citalopram 0.34 mixeddrug intoxication suicide available in four of the cases. The average fentanyl 0.01 peripheral blood to heart blood concentration atracurium (syringe) ratio was 1.6 (range 0.83-2.5). However, no 13 neg citalopram 0.43 epidural hematoma accident definitive conclusions can be drawn from brompheniramine 0.12 these limited data concerning the issue of postmortem redistribution of citalopram. * BAC = blood ethanol concentrations. t Muscle concentrations. The antemortem therapeutic concentration of citalopram is in the range of 0.2 mg/L (5,6). 642 Journal of AnalyticalToxicology, Vol. 25, October 2001 Cases 3, 6, and 11 had postmortem blood concentrations in this sibly ranging at least as high as 1.3 mg/L compared to its thera- range. Each of these cases had causes of death unrelated to peutic concentration of approximately 0.2 mg/L. It is also impor- citalopram use. Cases 1, 2, 4, 5, 7, 8, 12, and 13 had blood con- tant to note that concentrations of the parent drug are centrations greater than this reported therapeutic range, but less significantly greater than those of the desmethyl metabolite in than 1.3 mg/L.