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.

Pharmacogenetics and Genomics
Kathryn K Erickson-RidoutPhilip Lazarus

Abstract

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. 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. 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...Continue Reading

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Dec 11, 2014·European Journal of Drug Metabolism and Pharmacokinetics·Arne ReimersEylert Brodtkorb
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Jul 29, 2021·Pharmacogenetics and Genomics·Andrea J StanbridgeMeethu M Paul

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