The cytochrome P450 system is responsible for phase I oxidative metabolism of drugs. Following phase I metabolism, phase II metabolism makes the products of phase I metabolism more hydrophilic so that they can be more easily excreted. Due to this lesser role, phase II metabolism is generally less important in drug interactions (Sandson et al, 2005).
The most important family of enzymes for phase II metabolism is the uridine 5″-diphosphate
glucuronosyltransferases (UGTs). UGTs metabolize about 15% of FDA-approved medications (Dang et al., 2016). The metabolism of some psychotropic medications like lamotrigine and olanzapine occurs primarily through the UGTs.
The UGT system has some similarities to the CYP450 system. They:
1. Are also referred to be a number-letter-number notation.
2. Have various substrates, inhibitors, and inducers.
Medications metabolized by UGTs
Desvenlafaxine is metabolized by UGT1A1.
Lamotrigine is mainly metabolized by UGT1A4.
Olanzapine is mainly metabolized by CYP450 1A2 and UGT 1A4.
GeneSight® Psychotropic test includes testing for genetic polymorphisms of UGT1A4 and UGT2B15.
CNSDose® test includes testing for genetic polymorphisms of UGT1A1.
References
Cabaleiro T, López-Rodríguez R, Ochoa D, Román M, Novalbos J, Abad-Santos F. Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects. Hum Psychopharmacol. 2013 May;28(3):205-14. doi: 10.1002/hup.2308. PubMed PMID: 23559402.
Dang NL, Hughes TB, Krishnamurthy V, Swamidass SJ. A simple model predicts UGT-mediated metabolism. Bioinformatics. 2016 Oct 15;32(20):3183-3189. PubMed PMID: 27324196.
Du Z, Jiao Y, Shi L. Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children. Med Sci Monit. 2016 Oct 31;22:4107-4113. PubMed PMID: 27795544; PubMed Central PMCID: PMC5100833.
Erickson-Ridout KK, Sun D, Lazarus P. Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)₇TAA and UGT1A4 L48V polymorphisms. Pharmacogenet Genomics. 2012 Aug;22(8):561-76. PubMed PMID: 22565219
Erickson-Ridout KK, Zhu J, Lazarus P. Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants. Pharmacogenet Genomics. 2011 Sep;21(9):539-51. PubMed PMID: 21750471.
Gulcebi MI, Ozkaynakcı A, Goren MZ, Aker RG, Ozkara C, Onat FY. The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res. 2011 Jun;95(1-2):1-8. PubMed PMID: 21601426.
Ma H, Zhang T, Gong Z, Zhou B, Zou M, Xiao S, Zhu W. Effect of UGT2B7 genetic variants on serum valproic acid concentration. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2013 Aug;38(8):766-72. PubMed PMID: 23981985
Milosheska D, Lorber B, Vovk T, Kastelic M, Dolžan V, Grabnar I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. Br J Clin Pharmacol. 2016 Aug;82(2):399-411. doi: 10.1111/bcp.12984. PubMed PMID: 27096250; PubMed Central PMCID: PMC4972156.
Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005 Sep-Oct;46(5):464-94. Review. PubMed PMID: 16145193.
Spina E, de Leon J. Metabolic drug interactions with newer antipsychotics: a comparative review. Basic Clin Pharmacol Toxicol. 2007 Jan;100(1):4-22. Review. PubMed PMID: 17214606.
Stingl JC, Bartels H, Viviani R, Lehmann ML, Brockmöller J. Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review. Pharmacol Ther. 2014 Jan;141(1):92-116. PubMed PMID: 24076267.
Zhou D, Guo J, Linnenbach AJ, Booth-Genthe CL, Grimm SW. Role of human UGT2B10 in N-glucuronidation of tricyclic antidepressants, amitriptyline, imipramine, clomipramine, and trimipramine. Drug Metab Dispos. 2010 May;38(5):863-70. doi: 10.1124/dmd.109.030981. Epub 2010 Feb 4. PubMed PMID: 20133892.
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