The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053)

Calligaro, David O.; Fairhurst, John; Hotten, Terrence M.; Moore, Nicholas; Tupper, David E.

doi:10.1016/s0960-894x(96)00567-7

Cited by 31 publications

(20 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In subjects taking OLZ, unchanged OLZ comprises ~18% of total urinary OLZ, while OLZ glucuronides comprise nearly 61% of all urinary OLZ metabolites with the 10- N -glucuronide comprising ~67% of urinary OLZ glucuronides (29, 31, 32). While UGT1A4 was shown to be active against OLZ, several UGTs were not previously screened.…”

Section: Resultsmentioning

confidence: 99%

“…Other OLZ glucuronide products have been reported in humans including the directly conjugated OLZ-4’- N -glucuronide (18, 29, 31). In addition to increasing hydrophobicity and excretion of OLZ and its metabolites, glucuronidation deactivates the compound as evidenced by decreased binding to known OLZ receptors (32). Previous in vitro studies using over-expressing baculosomes demonstrated that UGT1A4 is active against OLZ, with no activity observed for UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants

Ridout¹,

Zhu²,

Lazarus

2011

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants

Ridout¹,

Zhu²,

Lazarus

2011

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

show abstract

“…in public transport. One very popular example of polymorphism exhibiting different colours as a function of the structure, hence the polymorph, is the 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, initially synthesized as an antipsychotic agent, 34 and also known as ROY (for Red, Orange, Yellow) ( Fig. 3), 35 which is probably one of the most famous and surprising compounds with respect to polymorphism.…”

Section: A5 Why So Much Interest In Polymorphs?mentioning

confidence: 99%

Polymorphism, what it is and how to identify it: a systematic review

Brog¹,

Chanez²,

Crochet³

et al. 2013

RSC Adv.

192

142

View full text Add to dashboard Cite

This review on polymorphism is a personal, non-comprehensive view on the field of polymorphism -a term which is often misused. Indeed, the discussion about polymorphism and related terms is still ongoing in the area of crystal engineering. This is why we felt it timely to look into the historical development of its definition and to delimit it. A short introduction to thermodynamic aspects and characterization methods of polymorphs is given. One chapter is then dedicated to polymorphism of elements and inorganic compounds, before discussing the term for organic and organo-metallic compounds. Chosen examples are given each time to illustrate the cases of polymorphism. In the end, the conclusion yields three flow schemes useful in determining polymorphism for each compound class.

show abstract

“…The 10-N-glucuronide is the most abundant metabolite, but the formation of 4-N-desmethylolanzapine is correlated with the clearance of OLA. All OLA metabolites are significantly less active than the parent compound [82]. A schematic drawing of metabolic pathways involved in the processing of OLA is reported in Fig.…”

Section: Pharmacokinetics and Interactionsmentioning

confidence: 99%

Antipsychotic and Antiepileptic Drugs in Bipolar Disorder: The Importance of Therapeutic Drug Monitoring

Musenga

Saracino

Sani³

et al. 2009

CMC

View full text Add to dashboard Cite

Bipolar disorder (BD) is a long-term illness with mood swings which are characterized by recurrent episodes of mania/hypomania and depression, with variable interpolations of relatively asymptomatic periods, called euthymic, in which, however, some psychopathological symptoms may persist. Although mood stabilizers, such as lithium, are the first-line treatment for the prevention of new BD episodes, combination therapy has become the standard of care for BD patients. Besides lithium, the use of a mood stabilizer along with an atypical antipsychotic is recommended in many patients. Recently, atypical antipsychotics (quetiapine, olanzapine, risperidone and aripiprazole) and antiepileptic agents (valproate, lamotrigine and oxcarbazepine) are increasingly used as mood stabilizers. To reduce side effects and optimize treatment it is important to perform accurate monitoring of drug blood levels in these patients, who are often treated with multiple drugs. Therapeutic drug monitoring (TDM) is in fact a powerful tool that, starting from clinical-chemical correlation data, allows to tailor-cut treatment to the specific needs of individual patients; hence the need to have reliable analytical methods available for the determination of plasma levels of drugs and their metabolites. Analyses of biological samples are mainly carried out using high-performance liquid chromatography (HPLC) coupled with different detectors, capillary electrophoresis and gas-chromatography. Various procedures are employed to remove biological interferences before analyzing the samples. This review focuses on currently available analytical TDM methods for atypical antipsychotics and antiepileptic agents used in the treatment of patients with bipolar disorder. Advantages and limitations of the various analytical methods will be reviewed and discussed, together with an evaluation of the role of TDM.

show abstract

The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053)

Cited by 31 publications

References 5 publications

Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants

Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants

Polymorphism, what it is and how to identify it: a systematic review

Antipsychotic and Antiepileptic Drugs in Bipolar Disorder: The Importance of Therapeutic Drug Monitoring

Contact Info

Product

Resources

About