Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants

Abstract

Olanzapine (OLZ) is an antipsychotic used in the treatment of schizophrenia, bipolar disorder, and treatment-resistant depression. Glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes is the major mode of OLZ metabolism and polymorphisms in these enzymes could contribute to inter-individual variability in OLZ metabolism and therapeutic response. In a screening of cell lines over-expressing individual UGTs, only UGTs 1A4 and 2B10 exhibited glucuronidation activity against OLZ. The UGT1A424Pro/48Val variant exhibited a 3.7-fold (p<0.0001) higher Vmax/KM for formation of the OLZ-10-N-glucuronide isomer 1 and a 4.3-fold (p<0.0001) higher Vmax/KM for formation of the OLZ-10-N-glucuronide isomer 2 than wild-type UGT1A424Pro/48Leu. The UGT2B1067Y variant exhibited no glucuronidation activity against OLZ. In a screening of 105 human liver microsomal (HLM) specimens, there was a 2.1- (p=0.04) and 1.6- (p=0.0017) fold increase in the rate of OLZ-10-N-glucuronide isomer 1 and OLZ-4’-N-glucuronide formation, and a 2.0-fold (p=0.02) increase in overall OLZ glucuronidation formation, in HLM with the UGT1A4 (*3/*3)/UGT2B10 (*1/*1) genotype compared to HLM with the UGT1A4 (*1/*1)/UGT2B10 (*1/*1) genotype. There was a 1.9-fold (p<0.003) decrease in formation of both isomers of the OLZ-10-N-glucuronide, a 2.7-fold (p<0.0001) decrease in OLZ-4’-N-glucuronide formation, and a 2.1-fold (p=0.0002) decrease in overall OLZ-glucuronide formation in HLM with at least one UGT2B10*2 allele. In regression analysis, both the UGT1A4*3 (p<0.02) and UGT2B10*2 (p<0.002) alleles were significant predictors of formation of all OLZ-glucuronide isomers. These data suggest that the UGT1A4*3 and UGT2B10*2 alleles contribute significantly to inter-individual variability in OLZ metabolism.

Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine

“…Polymorphisms in the coding region of the UGT1A4 gene may alter enzyme activity and thereby lead to reduced or enhanced elimination of LTG and, thus, altered serum concentrations. Previous studies on the effects of two common SNPs of the UGT1A4 gene, *2 and *3, found both unchanged, reduced, and enhanced enzyme activity (Chang et al 2014;Ehmer et al 2004;Erickson-Ridout et al 2011, Under 12 years, n (%) 6 (3 %)…”

Potential Role ofUGT1A4Promoter SNPs in Anastrozole Pharmacogenomics

“…Anastrozole glucuronidation was highly correlated with lamotrigine glucuronidation (a diagnostic substrate for UGT1A4; r = 0.99, P , 0.0001), 874 Edavana et al at ASPET Journals on May 11, 2018 dmd.aspetjournals.org but some recent studies suggest that lamotrigine may not be entirely specific for UGT1A4 (Erickson-Ridout et al, 2011). However, these results support the predominant (but not the sole) role of UGT1A4 in the direct glucuronidation of anastrozole.…”

Therapeutic drug monitoring of atypical antipsychotic drugs

“…The 10-N-glucuronide is the most abundant metabolite. Glucuronidation by the UDP-glucuronosyltransferase family of enzymes (1A4 and 2B10) is the major mode of olanzapine metabolism, and polymorphisms in these enzymes could contribute to interindividual variability in olanzapine metabolism and therapeutic response (44). Studies have shown that mean plasma olanzapine concentrations vary widely, depending on factors such as the prescribed daily dose and the duration of treatment (41).…”