title: ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram.
abstract: P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood-brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Karlsson
authors.forename: H
authors.initials: H
authors.lastname: Green
authors.forename: A L
authors.initials: AL
authors.lastname: Zackrisson
authors.forename: F
authors.initials: F
authors.lastname: Bengtsson
authors.forename: I
authors.initials: I
authors.lastname: Jakobsen Falk
authors.forename: B
authors.initials: B
authors.lastname: Carlsson
authors.forename: J
authors.initials: J
authors.lastname: Ahlner
authors.forename: F C
authors.initials: FC
authors.lastname: Kugelberg
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018687:Antidepressive Agents, Second-Generation / Q000506:poisoning*; D001344:Autopsy; D016022:Case-Control Studies; D015283:Citalopram / Q000506:poisoning*; D003511:Cyclohexanols / Q000506:poisoning*; D062787:Drug Overdose / Q000235:genetics*; D005260:Female; D053803:Forensic Genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D000069470:Venlafaxine Hydrochloride
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D015283:Citalopram; D000069470:Venlafaxine Hydrochloride