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 R-
ornidazole 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 ± 1.6 mM for R-
ornidazole) and 2B7 (3.8 ± 0.9 mM for S-
ornidazole) were quite similar to those determined in HLMs and HKMs (20.1 ± 1.4 and 17.7 ± 4.0 mM for R-
ornidazole; 6.6 ± 1.3 and 3.2 ± 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 well-stirred 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.