Abstract

Morinidazole [R,S-1-(2-methyl-5-nitro-1H-imidazol-1-yl)-3-morpholinopropan-2-ol] is a new 5-nitroimidazole class antimicrobial agent. The present study aimed to determine the metabolism and pharmacokinetics of morinidazole in humans and to identify the enzymes responsible for the formation of the major metabolites. Plasma and urine samples were collected before and after an intravenous drip infusion of 500 mg of racemic morinidazole. Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 10 metabolites. Morinidazole glucuronidation, followed by renal excretion, was the major elimination pathway, accounting for 35% of the dose. The metabolic pathway displayed regioselectivities and stereoselectivities. Unexpectedly, the nitrogen atom of the morpholine ring, rather than the aliphatic hydroxyl group at the side chain, was glucuronidated to form S-morinidazole glucuronide (M8-1) and R-enantiomer glucuronide (M8-2). The plasma exposure of M8-2 was 6-fold higher than that of M8-1, accounting for 22.9 and 3.96% of the parent drug exposure, respectively. Investigation of morinidazole glucuronidation using human liver microsomes (HLMs) and 12 recombinant UDP glucuronosyltransferases (UGTs) indicated that this biotransformation was mainly catalyzed by UGT1A9. A kinetic study showed that N⁺-glucuronidation of racemic morinidazole in both HLMs and in UGT1A9 obeyed a typical Michaelis-Menten plot. The K_m values for M8-1 and M8-2 formation by HLMs were similar (11.3 and 15.1 mM), but the V_max values were significantly different (111 and 1660 pmol · min⁻¹ · mg protein⁻¹). Overall, after an intravenous administration, morinidazole and its metabolites were eliminated in humans primarily via renal excretion. The major metabolites were two diastereoisomeric N⁺-glucuronides, and UGT1A9 played an important role in N⁺-glucuronidation.