K. Erickson-Ridout, Dongxiao Sun, P. Lazarus
Aug 1, 2012
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Influential Citations
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Journal
Pharmacogenetics and Genomics
Abstract
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 Vmax/KM 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 UGT1A424Pro/48Val variant showed a 5.2-, 2.0-, and 3.4-fold (P<0.0001 for all) higher Vmax/KM for the formation of CLZ-5-N-glucuronide, CLZ-N+-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-type UGT1A424Pro/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.