INTRODUCTION: Clozapine (CLZ) is an FDA approved second-generation antipsychotic for refractory schizophrenia, and glucuronidation is an important pathway in its metabolism. The aim of this study was to fully characterize the CLZ glucuronidation pathway and examine whether polymorphisms in active glucuronidating enzymes could contribute to variability in CLZ metabolism. METHODS: Cell lines overexpressing wild-type or variant uridine diphosphate-glucuronosyltransferase (UGT) enzymes were used to determine which UGTs show activity against CLZ and its major active metabolite N-desmethylclozapine (dmCLZ). Human liver microsomes (HLM) were used to compare hepatic glucuronidation activity against the UGT genotype. RESULTS: Several UGTs including 1A1 and 1A4 were active against CLZ; only UGT1A4 showed activity against dmCLZ. UGT1A1 showed a 2.1-fold (P <0.0001) higher V(max)/K(M) for formation of the CLZ-N⁺-glucuronide than UGT1A4; UGT1A4 was the only UGT for which CLZ-5-N-glucuronide kinetics could be determined. The UGT1A4(24Pro/48Val) variant showed a 5.2-, 2.0-, and 3.4-fold (P < 0.0001 for all) higher V(max)/K(M) for the formation of CLZ-5-N-glucuronide, CLZ-N⁺-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-type UGT1A4(24Pro/48Leu). There was a 37% (P< 0.05) decrease in the rate of CLZ-N⁺-glucuronide formation in HLM with the UGT1A1 (*28/*28)/UGT1A4 (*1/*1) genotype, and a 2.2- and 1.8-fold (P < 0.05 for both) increase in the formation of CLZ-5-N-glucuronide and CLZ-N⁺-glucuronide in UGT1A1 (*1/*1)/UGT1A4 (*3/*3) HLM compared with UGT1A1 (*1/*1)/UGT1A4 (*1/*1) HLM. The UGT1A1*28 allele was a significant (P = 0.045) predictor of CLZ-N⁺-glucuronide formation; the UGT1A4*3 allele was a significant (P < 0.0001) predictor of CLZ-5-N-glucuronide and dmCLZ-glucuronide formation. CONCLUSION: These data suggest that the UGT1A1*28 and UGT1A4*3 alleles contribute significantly to the interindividual variability in CLZ and dmCLZ metabolism.
INTRODUCTION:Clozapine (CLZ) is an FDA approved second-generation antipsychotic for refractory schizophrenia, and glucuronidation is an important pathway in its metabolism. The aim of this study was to fully characterize the CLZ glucuronidation pathway and examine whether polymorphisms in active glucuronidating enzymes could contribute to variability in CLZ metabolism. METHODS: Cell lines overexpressing wild-type or variant uridine diphosphate-glucuronosyltransferase (UGT) enzymes were used to determine which UGTs show activity against CLZ and its major active metabolite N-desmethylclozapine (dmCLZ). Human liver microsomes (HLM) were used to compare hepatic glucuronidation activity against the UGT genotype. RESULTS: Several UGTs including 1A1 and 1A4 were active against CLZ; only UGT1A4 showed activity against dmCLZ. UGT1A1 showed a 2.1-fold (P <0.0001) higher V(max)/K(M) for formation of the CLZ-N⁺-glucuronide than UGT1A4; UGT1A4 was the only UGT for which CLZ-5-N-glucuronide kinetics could be determined. The UGT1A4(24Pro/48Val) variant showed a 5.2-, 2.0-, and 3.4-fold (P < 0.0001 for all) higher V(max)/K(M) for the formation of CLZ-5-N-glucuronide, CLZ-N⁺-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-type UGT1A4(24Pro/48Leu). There was a 37% (P< 0.05) decrease in the rate of CLZ-N⁺-glucuronide formation in HLM with the UGT1A1 (*28/*28)/UGT1A4 (*1/*1) genotype, and a 2.2- and 1.8-fold (P < 0.05 for both) increase in the formation of CLZ-5-N-glucuronide and CLZ-N⁺-glucuronide in UGT1A1 (*1/*1)/UGT1A4 (*3/*3) HLM compared with UGT1A1 (*1/*1)/UGT1A4 (*1/*1) HLM. The UGT1A1*28 allele was a significant (P = 0.045) predictor of CLZ-N⁺-glucuronide formation; the UGT1A4*3 allele was a significant (P < 0.0001) predictor of CLZ-5-N-glucuronide and dmCLZ-glucuronide formation. CONCLUSION: These data suggest that the UGT1A1*28 and UGT1A4*3 alleles contribute significantly to the interindividual variability in CLZ and dmCLZ metabolism.
Authors: S F M van de Wetering-Krebbers; P L Jacobs; G J Kemperman; E Spaans; P A M Peeters; L P C Delbressine; M L P S van Iersel Journal: Drug Metab Dispos Date: 2010-12-22 Impact factor: 3.922
Authors: Andrea S Blevins-Primeau; Dongxiao Sun; Gang Chen; Arun K Sharma; Carla J Gallagher; Shantu Amin; Philip Lazarus Journal: Cancer Res Date: 2009-02-24 Impact factor: 12.701
Authors: Dongxiao Sun; Gang Chen; Ryan W Dellinger; Kimberly Duncan; Jia-Long Fang; Philip Lazarus Journal: Breast Cancer Res Date: 2006 Impact factor: 6.466
Authors: Isabella R Willcocks; Sophie E Legge; Mariana Nalmpanti; Lucy Mazzeo; Adrian King; John Jansen; Marinka Helthuis; Michael J Owen; Michael C O'Donovan; James T R Walters; Antonio F Pardiñas Journal: Front Pharmacol Date: 2021-04-16 Impact factor: 5.810
Authors: Karlijn Pellikaan; Yassine Ben Brahim; Anna G W Rosenberg; Kirsten Davidse; Christine Poitou; Muriel Coupaye; Anthony P Goldstone; Charlotte Høybye; Tania P Markovic; Graziano Grugni; Antonino Crinò; Assumpta Caixàs; Talia Eldar-Geva; Harry J Hirsch; Varda Gross-Tsur; Merlin G Butler; Jennifer L Miller; Paul-Hugo M van der Kuy; Sjoerd A A van den Berg; Jenny A Visser; Aart J van der Lely; Laura C G de Graaff Journal: J Clin Med Date: 2021-12-10 Impact factor: 4.241