Slučaj trovanja sa fatalnim ishodom koji uključuje interakciju lekova zbog inhibicije citohroma P450
Sažetak
Uvod. Enzimi citohroma P450 (CYP) su odgovorni za metabolizam različitih lekova i hemikalija. Forenzički patolog treba da razmotri ne samo farmakodinamske interakcije između više lekova već i farmakokinetičke interakcije svakog leka u slučaju multiple ingestije lekova. Prikaz bolesnika. Žena u 40-im godinama, na lečenju od zavisnosti od alkohola, nađena je mrtva u svojoj kući. Medikolegalnom autopsijom nisu nađeni znaci koji bi upućivali na prirodni uzrok smrti. Kvantitativnom toksikološkom analizom nađeno je da su koncentracije levomepromazina, prometazina, dekstrometorfana, estazolama, klomipramina, risperidona i flunitrazepama u femoralnoj krvi bile: 0.750 µg/mL, 0.701 µg/mL, 0.332 µg/mL, 0.390 µg/mL, 0.216 µg/mL, 0.031 µg/mL, i 0.002 µg/mL, redom, uz etil alkohol u krvi u koncentraciji od 377 mg/dL. Zaključak. Zaključili smo da je uzrok smrti bila interakcija između etil alkohola i više psihotropnih lekova. Farmakokinetičke interakcije lekova zbog inhibicije CYP trebalo bi uzeti u obzir kod procene toksičnosti u slučajevima trovanja koji uključuju ingestiju više lekova.
Reference
Kinoshita H, Tanaka N, Takakura A, Kumihashi M, Jamal M, Ito A, et al. Multiple drug poisoning case caused by a pharmacoki-netic interaction involving paroxetine. Rom J Leg Med 2015; 23(3): 208‒10.
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug me-tabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013; 138(1): 103‒41.
Lynch T, Price A. The effects of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76(3): 391‒6.
Wilkinson GR. Drug metabolism and variability among pa-tients in drug response. N Engl J Med 2005; 352(21): 2211‒21.
Flockhart DA. Drug Interactions: Cytochrome P450 Drug In-teraction Table. Indiana University School of Medicine. (2007). Available from:
https://drug-interactions.medicine.iu.edu/Home.aspx [ac-cessed 2019 April 3].
Kinoshita H, Tanaka N, Takakura A, Kumihashi M, Jamal M, Ito A, et al. Flunitrazepam in stomach contents may be a good in-dicator of its massive ingestion. Rom J Leg Med 2017; 25(2): 193‒5.
Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. Thera-peutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics. Crit Care 2012; 16(4): R136.
Baselt RC. Disposition of toxic drugs and chemicals in man. 8th ed. Foster City, CA: Biomedical Publications; 2008.
Drummer OH, Odell M. The forensic pharmacology of drug of abuse. London: Arnold; 2001.
Koski A, Ojanperä I, Vuori E. Interaction of alcohol and drugs in fatal poisonings. Hum Exp Toxicol 2003; 22(5): 281‒7.
Gervasini G, Caballero MJ, Carrillo JA, Benitez J. Comparative cytochrome p450 in vitro inhibition by atypical antipsychotic drugs. ISRN Pharmacol 2013; 2013: 792456.
Basińska-Ziobroń A, Daniel WA, Wǒjcikowski J. Inhibition of human cytochrome P450 isoenzymes by a phenothiazine neu-roleptic levomepromazine: An in vitro study. Phramacol Rep 2015; 67(6): 1178‒82.
Vandel P, Haffen E, Nezelof S, Broly F, Kantelip JP, Sechter D. Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients. Hum Psychopharmacol 2004; 19(5): 293‒8.
Suzuki A, Yasui-Furukori N, Mihara K, Kondo T, Furukori H, In-oue Y, et al. Histamine H1-receptor antagonists, promethazine and homochlorcyclizine, increase the steady-state plasma con-centrations of haloperidol and reduced haloperidol. Ther Drug Monit 2003; 25(2): 192‒6.
Frank D, Jaehde U, Fuhr U. Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol 2007; 63(4): 321‒33.
Miura M, Otani K, Ohkubo T. Identification of human cyto-chrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam. Xenobiotica 2005; 35(5): 455–65.
Kilicarslan T, Haining RL, Rettie AE, Busto U, Tyndale RF, Sellers EM. Flunitrazepam metabolism by cytochrome P450s 2C19 and 3A4. Drug Metab Dispos 2001; 29(4 Pt 1): 460‒5.
Forget P, le Polain de Waroux B, Wallenmacq P, Gala JL. Life-threatening dextromethorphan intoxication associated with interaction with amitriptyline in a poor CYP2D6 metabolizer: a single case re-exposure study. J Pain Symptom Manage 2008; 36(1): 92‒6.
Adachi Y, Uchisaki S, Itagaki T, Suzuki K, Obata Y, Doi M, et al. Serotonin syndrome caused by an overdose of dextrome-thorphan, Medicon®. Masui 2009; 58(12): 1531‒3. (Japanese)