Clinical Pharmacology and Side Effects of Antipsychotic and Mood-Stabilizing Drugs used in the Treatment of Psychiatric Patients with Chronic or Recurrent Disorders

Baldessarini, Ross J.

doi:10.1007/978-94-011-6308-8_13

Cited by 1 publication

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“…Severe weight gain and obesity are seen in a subset of patients taking OLZ (23) and the evidence suggests that there is a dose-response relationship between OLZ serum concentrations and metabolic outcomes (24–27). Acute OLZ administration results in lower basal and peak glucose levels and lower insulin response to oral glucose tolerance tests, while increasing circulating leptin (28).…”

Section: Introductionmentioning

confidence: 99%

Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants

Ridout¹,

Zhu²,

Lazarus

2011

Pharmacogenetics and Genomics

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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.

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