Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics

Abstract

Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase (COMT), other enzymes (e.g., UGT1A1 or UGT1A4), and transporters (e.g., SLCO1B1, ABCB1, or ABCG2). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine’s metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings.

The Pharmacogenetics of Treatment with Quetiapine

“…For instance, COMT is known to play an important role in the effectiveness of many antipsychotics due to its role in dopamine degradation, as the dopaminergic system is important in antipsychotic activ-ity [14]. However, a recent study suggests that a portion of quetiapine may be metabolized by this enzyme [5]; in the latter work, the COMT rs13306278 T led to the accumulation of a metabolite (7,8-dihydroxy-N-desalkyl quetiapine), which was suggested to inhibit CYP3A4, causing the accumulation of quetiapine and therefore an increased risk for ADRs; nonetheless, additional studies are warranted to confirm this hypothesis [5].…”

“…Quetiapine is around 83% bound to plasma proteins [4]. It is extensively metabolized in the liver by the cytochrome P450 (CYP) system, presenting less than 5% of the original drug in the excretions, mostly in urine (approximately 73%) and feces (21%) [4,5]. CYP3A4 metabolizes 89% of quetiapine's dose, and the other 11% is metabolized mainly by CYP2D6 and other enzymes, namely CYP3A5, CYP2C9 and CYP2C19 [1,6].…”

“…Furthermore, quetiapine is a CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibitor [1]. Additionally, recent studies suggest the participation of the catechol O-methyltransferase (COMT) enzyme in quetiapine's intermediate metabolism (Figure 1) [5].…”

“…(CYP) system, presenting less than 5% of the original drug in the excretions, mo urine (approximately 73%) and feces (21%) [4,5]. CYP3A4 metabolizes 89% of quetia dose, and the other 11% is metabolized mainly by CYP2D6 and other enzymes, n CYP3A5, CYP2C9 and CYP2C19 [1,6].…”

“…Furthermore, quetiapine is a CYP1A2, CYP2C9, CYP2C19, CY and CYP3A4 inhibitor [1]. Additionally, recent studies suggest the participation catechol O-methyltransferase (COMT) enzyme in quetiapine's intermediate meta (Figure 1) [5]. Although its precise mechanism of action remains controversial, it is a seroto HT2 receptor antagonist (HTR2) and a dopamine D1 and D2 receptor (DRD1 and D antagonist with affinity for other receptors, such as histamine H1, muscarinic M1, M M5, α1-adrenergic and other serotonin receptors.…”