N-methylation of BI 187004 by thiol S-methyltransferase

• Published in: Drug metabolism and disposition Vol. 46; no. 6; pp. 770 - 778
• Main Authors: Maw, Hlaing H, Zeng, Xingzhong, Campbell, Scot, Taub, Mitchell E, Teitelbaum, Aaron M
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics, Inc 01.06.2018
• Subjects: 11β-Hydroxysteroid dehydrogenase; Amodiaquine; Biotransformation; Catechol; Catechol O-methyltransferase; Cytosol; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Enzymes; Glycine; Glycine N-methyltransferase; Histamine; Histamine N-methyltransferase; Inhibitors; Kidneys; Liver; Methylation; Methyltransferase; Microsomes; N-Methyltransferase; Nicotinamide; Nicotinamide N-methyltransferase; Organic chemistry; Patients; Substrates; Thiol S-methyltransferase; Thiopurine S-methyltransferase; methylation/methyl transferase; human/clinical; pharmacogenetics/pharmacogenomics; metabolite identification
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.117.079764

BI 187004, an 11β-hydroxysteroid dehydrogenase 1 (HSD) inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N-methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite (M1) was 7 fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzyme(s) responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O-methyltransferase (rhCOMT), histamine N-methyltransferase (rhHNMT), nicotinamide N-methyltransferase (rhNNMT), glycine N-methyltransferase (rhGNMT), and thiopurine S-methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, formation of M1 was only inhibited by 2,3-dichloro-α-methylbenzylamine (DCMB), an inhibitor of thiol S-methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N-methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N-methylation biotransformation and an HNMT-mediated regioselective N-methylation.