Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10

Abstract

OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (K m = 3.4 6 0.2 mM), intestinal microsomes (HIM) (K m = 1.7 6 0.1 mM), and UGTs. UGT1A1 (64 ml/min/ mg) and UGT1A8 (72 ml/min/mg) exhibited the highest intrinsic clearances (CL int ) for OTS167, followed by UGT1A3 (51 ml/min/mg) and UGT1A10 (47 ml/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0-21%) was observed using clinically relevant OTS167 concentrations (0.4-2 mM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to firstpass OTS167 metabolism after oral administration.

Combined study of genetic and epigenetic biomarker risperidone treatment efficacy in Chinese Han schizophrenia patients

“… 18 , 19 For example, effect of rs6706232 on OTS167 (a novel synthetic anticancer agent molecule undergoing clinical development) glucuronidation formation rates was merely modest suggesting this SNP may not significantly contribute to OTS167 clearance. 20 In our study, rs6706232 was first found related with risperidone treatment in mainland Chinese Han population, allele A accounted for a higher proportion in good responders compared with poor responders at 33.3%, 24.6%, 25.2% in the Henan, Shanghai and total cohort, respectively, which means the G>A mutation might have certain impact on risperidone therapy. Recent research found that rs6706232 was significantly associated with UGT1A3 gene transcription and activity.…”

MetScore: Site of Metabolism Prediction Beyond Cytochrome P450 Enzymes

“…Second, there are some additional transformations with no training data evidence that we nevertheless kept in the validation set. For molecule 13 a “hypothesized glucuronide” is reported, an atypical N ‐glucuronide adduct to a pyridine ring. Molecules 18 and 23 show isoxazole ring cleavages.…”

Identification and characterization of the structure–activity relationships involved in UGT1A1 inhibition by anthraquinone and dianthrone constituents of Polygonum multiflorum

“…However, some quinines inhibit UGTs, leading to adverse reactions. For example 44 , OTS167, an antineoplastic agent, is metabolized mainly by UGT1A1 and UGT1A3, and is inhibited by emodin (an inhibitor of UGT1A8 and UGT1A10). At the concentrations required to exert an antitumor effect, celastrol interacts with herbs and drugs 45 .…”