Contributions of UDP-Glucuronosyltransferases to Human Hepatic and Intestinal Metabolism of Ticagrelor and Inhibition of UGTs and Cytochrome P450 Enzymes by Ticagrelor and its Glucuronidated Metabolite

Abstract

Ticagrelor is the first reversibly binding, direct-acting, oral P2Y12 receptor inhibitor. The contribution of UDP-glucuronosyltransferases (UGTs) enzymes to the metabolism of ticagrelor to its glucuronide conjugation, ticagrelor-O-glucuronide, in human liver microsomes (HLM) and human intestinal microsomes (HIM), was well characterized in the current study. The inhibition potential of human major UGTs by ticagrelor and ticagrelor-O-glucuronide was explored. The inhibitory effects of ticagrelor-O-glucuronide on cytochrome P450s (CYPs) enzymes were investigated as well. Ticagrelor glucuronidation exhibits substrate inhibition kinetics in both HLM and HIM with apparent Km values of 5.65 and 2.52 μM, Vmax values of 8.03 and 0.90 pmol min−1·mg protein−1, Ksi values of 1,343.0 and 292.9 respectively. The in vitro intrinsic clearances (Vmax/Km) for ticagrelor glucuronidation by HLM and HIM were 1.42 and 0.36 μl min−1·mg protein−1, respectively. Study with recombinant human UGTs suggested that multiple UGT isoforms including UGT1A9, UGT1A7, UGT1A3, UGT1A4, UGT1A1, UGT2B7 and UGT1A8 are involved in the conversion of ticagrelor to ticagrelor-O-glucuronide with UGT1A9 showing highest catalytic activity. The results were further supported by the inhibition studies on ticagrelor glucuronidation with typical UGT inhibitors in pooled HLM and HIM. Little or no inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 by ticagrelor and ticagrelor-O-glucuronide was noted. Ticagrelor-O-glucuronide also exhibited limited inhibitory effects toward CYP2C8, CYP2D6 and CYP3A4. In contrast, ticagrelor-O-glucuronide weakly inhibited CYP2B6, CYP2C9 and CYP2C19 activity with apparent IC50 values of 45.0, 20.0 and 18.8 μM, respectively. The potential of ticagrelor-O-glucuronide to cause drug-drug interactions warrant further study.

Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC–MS method

“…Furthermore, our findings suggest that N -hydap downregulated the enzymatic activity of most DMEs in the liver, while it was interesting that the activity of several enzymes in the kidneys tended to be either opposite or unchanged. Literature reports suggest that drug metabolites can inhibit CYPs and UGTs [ 30 ]. Enzyme kinetic analysis of N -hydap glucuronidation revealed that liver microsomes exhibited a stronger affinity for N -hydap (lower K m value) and a faster conversion rate of N -hydap to N -hydap-G (higher CL int value) compared to renal microsomes in humans, rats and mice.…”

Physiologically Based Pharmacokinetic Modeling to Predict the Impact of Liver Cirrhosis on Glucuronidation via UGT1A4 and UGT2B7/2B4—A Case Study with Midazolam

“…This low bioavailability is the result of intestinal metabolism primarily driven by UGT1A9 and UGT1A10, leading to a pronounced intestinal first-pass effect (Mizuma, 2009;Ritter, 2007). Another example is ticagrelor, for which in vitro studies in human intestinal microsomes indicated a glucuronidation activity and additional evaluation in recombinant system confirmed the implication of UGT1A9 (main) and UGT1A7, UGT1A3, UGT1A4, UGT1A1, UGT2B7 and UGT1A8 as enzymes involved in its metabolism (Liu et al, 2021).…”

Pharmacogenetics ofP2Y12receptor inhibitors

“…Ticagrelor undergoes oxidation primarily via CYP3A4, and to a lesser extent CYP3A5, to produce an active metabolite (AR-C124910XX [also known as M8]), which has concentrations that are about one-third of the parent drug with equivalent potency. [13][14][15][16]…”

“…Ticagrelor is a substrate for both P‐gp in the intestine and the solute carrier organic anion transporter family member 1B1 (SLCO1B1) in the liver and undergoes glucuronidation via multiple UDP‐glucuronosyltransferase (UGT) isoforms (e.g., UGT1A9, UGT1A7, and UGT2B7) to form a glucuronide conjugate. Ticagrelor undergoes oxidation primarily via CYP3A4, and to a lesser extent CYP3A5, to produce an active metabolite (AR‐C124910XX [also known as M8]), which has concentrations that are about one‐third of the parent drug with equivalent potency 13‐16 …”