Stereoselective Glucuronidation of Ornidazole in Humans: Predominant Contribution of UDP-Glucuronosyltransferases 1A9 and 2B7

Abstract

Ornidazole [R,S-1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol] is a chiral 5-nitroimidazole class antimicrobial agent. This study aimed to investigate the principal metabolic pathway of ornidazole in humans and identify the major enzymes involved. A total of 19 metabolites were identified in human urine collected from patients with hepatobiliary diseases after an intravenous drip infusion of 500 mg of racemic ornidazole. Stereoselective glucuronidation, followed by renal excretion, was the principal metabolic pathway of ornidazole in humans, accounting for 37.3% of the administered dose. Screening assays with 12 available human recombinant UDP-glucuronosyltransferases (UGTs) demonstrated that UGT1A9 was the predominant UGT isoform involved in Rornidazole glucuronidation, whereas S-ornidazole glucuronidation was almost exclusively catalyzed by UGT2B7. Chemical inhibition study with niflumic acid and flurbiprofen supported these findings. Enzyme kinetic parameters were then determined in human liver microsomes (HLMs), human kidney microsomes (HKMs), UGT1A9, and 2B7. The K m values for UGT1A9 (15.6 6 1.6 mM for R-ornidazole) and 2B7 (3.8 6 0.9 mM for S-ornidazole) were quite similar to those determined in HLMs and HKMs (20.1 6 1.4 and 17.7 6 4.0 mM for R-ornidazole; 6.6 6 1.3 and 3.2 6 0.4 mM for S-ornidazole). The in vitro intrinsic clearance (CL int ) ratios of S-to R-ornidazole were approximately 4.3 in HLMs and 6.5 in HKMs, respectively. The hepatic and renal clearances were estimated based on the wellstirred model. Overall, stereoselective glucuronidation was the principal metabolic pathway of ornidazole in humans. Furthermore, UGT1A9 and 2B7 were the predominant UGT isoforms responsible for R-and S-ornidazole glucuronidation in humans, respectively.

The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms

“…UGT1A4 is well-known for its N-glucuronidation activity and has numerous endogenous substrates such as proges- 769) Gaboxadol (114) Hydroxywarfarin (808) Mycophenolic acid (49) Nebicapone (methyltransferase inhibitor) (417) Nicotine (371) NSAIDs (184,444) Ornidazole (153) Oxazepam (132) Oxymetazoline (440) Propofol (131) Propranolol (249,667) Resveratrol (307) SAHA (20) Sorafenib ( 563 542) Chloramphenicol ( 98) Codeine ( 589) Efavirenz (antiviral) (43) Epirubicin (295) Gemfibrozil (446) Haloperidol (343) Lorazepam (736) Lorcaserin (anti-obesity drug) (615) Morphine (124) Mycophenolic acid (569) NSAIDs (184,315,317,445), Ornidazole (153) Valproic acid (13) Continued tins (e.g., 5␣-pregnane-3␣,20␣-diol) (220), dihydrotestosterone (DHT) and trans-androsterone (164,220,803), and 25-hydroxyvitamin D 3 (755). UGT1A4 conjugates nondrug xenobiotics such as sapogenins (i.e., hecogenin, diosgenin, tigogenin) (220), nicotine (720), and the nicotine-derived tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNAL) (a wellknown lung carcinogen) (760).…”

Structure- and isoform-specific glucuronidation of six curcumin analogs

“…In fact, UGT1A9 and UGT2B7 showed glucuronidation activities toward a broad range of compounds containing an alcoholic hydroxyl group. These compounds include 1 0 -hydroxyestragole (Iyer et al, 2003), 3 0 -azido-3 0 -deoxythymidine (Barbier et al, 2000), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Ren et al, 2000), 4-hydroxyretinoic acid (Samokyszyn et al, 2000), almokalant (Gaiser et al, 2003), bicalutamide (Grosse et al, 2013), dihydroartemisinin (Ilett et al, 2002), ethanol (Al Saabi et al, 2013Schwab & Skopp, 2014), ornidazole (Du et al, 2013), propafenone (Xie and Zeng, 2010), propranolol (Yu et al, 2010) and R-oxazepam (Court et al, 2002). It should be noted that both hepatic and renal UGTs would contribute to the metabolism of these curcumin analogs, because UGT1A9 and UGT2B7 were abundantly expressed in human liver and kidney (Fallon et al, 2013a;Sato et al, 2014).…”

Ornidazole Transfer into Colostrum and Assessment of Exposure Risk for Breastfeeding Infant: A Population Pharmacokinetic Analysis

“…It has an elimination half-life of 11-14 h, which is approximately 1.7 times that of metronidazole [6][7][8]. Ornidazole is mainly metabolized in the liver through glucuronidation, with other metabolic pathways including oxidation and hydrolysis [9]. The majority of the prodrug and its metabolites are eliminated by the kidneys and excreted in the urine (about 70%), and only a small fraction is excreted in the bile and feces (about 20%) [10].…”