Metabolism of Quetiapine by CYP3A4 and CYP3A5 in Presence or Absence of Cytochrome B₅

Abstract

ABSTRACT:The antipsychotic drug quetiapine is extensively metabolized by CYP3A4, but little is known about the possible influence of the polymorphic enzyme CYP3A5. This in vitro study investigated the relative importance of CYP3A4 and CYP3A5 in the metabolism of quetiapine and compared the metabolic pattern by the two enzymes, in the presence or absence of cytochrome b 5 . Intrinsic clearance (CL int ) of quetiapine was determined by the substrate depletion approach in CYP3A4 and CYP3A5 insect cell microsomes with or without coexpressed cytochrome b 5 . Formation of the metabolites quetiapine sulfoxide, N-desalkylquetiapine, O-desalkylquetiapine, and 7-hydroxyquetiapine by CYP3A4 and CYP3A5 were compared in the different microsomal preparations. CL int of quetiapine by CYP3A5 was less than 35% relative to CYP3A4. Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic drug used for the treatment of schizophrenia and acute episodes of mania. Recently, the U.S. Food and Drug Administration also approved quetiapine for the treatment of depressive episodes associated with bipolar disorder.Quetiapine is extensively metabolized in the liver by the cytochrome P450 (P450) system, primarily by CYP3A (Grimm et al., 1997(Grimm et al., , 2006. The major metabolic pathways of quetiapine are through sulfoxidation, N-and O-dealkylation, and, to a lesser degree, through 7-hydroxylation (Grimm et al., 1997) (Fig. 1). The pharmacologically inactive metabolite quetiapine sulfoxide is considered to be the main metabolite of quetiapine (DeVane and Nemeroff, 2001), whereas the most important active metabolite seems to be N-desalkylquetiapine (McIntyre et al., 2007). Studies indicate that N-desalkylquetiapine, unlike the parent compound, is a potent inhibitor of the noradrenergic transporter and has partial agonist activity at the 5-hydroxytryptamine 1A receptor (Goldstein et al., 2007;Jensen et al., 2008). In addition, N-desalkylquetiapine was found to possess antidepressive-like activity in a mouse model (Jensen et al., 2008). This suggests that the antidepressive activity of quetiapine is, at least partly, mediated by N-desalkylquetiapine. The active metabolite 7-hydroxyquetiapine is formed by CYP2D6 in addition to by CYP3A (Grimm et al., 2006). Because of the low plasma concentration of this metabolite (Gefvert et al., 1998), genetic polymorphism in CYP2D6 is unlikely to be of importance for the in vivo metabolism of quetiapine.CYP3A4 and CYP3A5 comprise the two main CYP3A isoforms in adults. The individual variability in phenotype is substantial for both enzymes, but this variability is linked to genetic polymorphism only for CYP3A5 (Westlind-Johnsson et al., 2003). CYP3A5 is expressed in approximately 10 to 30% of whites, 30% of Japanese, and 60% of African Americans (Kuehl et al., 2001;Burk and Wojnowski, 2004). The relative contribution of CYP3A5 to total hepatic CYP3A protein differs, but in some individuals CYP3A5 can constitute more than 50% of total CYP3A (Kuehl et al., 2001;Lin et al., 2002; WestlindJohns...

Metabolism of the Active Metabolite of Quetiapine,N-Desalkylquetiapine In Vitro

“…Thus, the calculated CL int of N-desalkylquetiapine by CYP3A4 in the present study could potentially have been higher in microsomes coexpressed with cytochrome b 5 . However, the effect of cytochrome b 5 on CYP3A4 activity is substrate-specific (Yamaori et al, 2003), and we have previously shown that the in vitro metabolism of quetiapine was actually lower in recombinant CYP3A4 coexpressed with cytochrome b 5 (Bakken et al, 2009). The CL int value for CYP3A4-mediated metabolism is also more uncertain compared with CYP2D6, because the substrate loss in CYP3A4 microsomes was less than recommended (Jones and Houston, 2004).…”

“…CYP3A is the main enzyme involved in the metabolism of quetiapine, responsible for the sulfoxidation, N-and O-dealkylation, and partially the 7-hydroxylation (Grimm et al, 1997;Bakken et al, 2009). The 7-hydroxy pathway is also catalyzed by CYP2D6 (Grimm et al, 2006), but this enzyme is of minor importance for the overall clearance of quetiapine (Hasselstrøm and Linnet, 2006).…”

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

“…34) The V max /K m of quetiapine with cytochrome b 5 was less than 35% that of CYP3A4, and V max /K m for CYP3A4 without cytochrome b 5 was 3 times that of CYP3A4 with coexpressed cytochrome b 5 , whereas for CYP3A5, V max /K m was similar for both microsomal preparations. 66) Further detailed studies on the contribution of cytochrome b 5 are required in the future.…”

“…For these 73 (Table 3). [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] The mean (± S.D.) and median CYP3A5/CYP3A4 ratios of the metabolic activities in these 47 reactions were 0.69 ± 1.23 and 0.28, respectively.…”

Coexpression of Genetically Engineered Cyt b5-CYP3A4 Fusion Protein with POR in Sf9 Insect Cells and Functional Characterization of the Expressed Products in vitro

“…Therefore, many in vitro studies relied on recombinant CYP3A4 as screening tool to evaluate potential drug-drug interactions (DDIs) in vivo. For this purpose, catalytically active recombinant human CYP3A4 isoform has been successfully expressed in E. coli [12], yeast [13], mammalian cells [14,15] and insect cells [16]. Meanwhile, different techniques have also been employed to enhance the enzymatic activity of recombinant CYP3A4, like co-expression and protein fusion [17][18][19].…”