N-oxidation: a possible route of tinidazole metabolism in man

Abstract

Treatment of tinidazole with a mixture of hydrogen peroxide and acetic acid, or liver homogenate preparations, yields the N-3 oxide. This was identified by thin-layer chromatographic analysis on silica gel G, R, 0.6, using ethanol-chloroform-ammonia (50:49:1) as solvent, and by chemical reduction with Sulphur dioxide. UV spectrophotometry and high performance liquid chromatography (HPLC ) gave an RT of 0.55 min using Pye Unicam apparatus equipped with a UV detector at 330 nm, a reversed-phase RP 18 (10 µm) column which was 12.5 cm long, a mobile phase of methanol 0.005 M KH2PO4 ( pH 4) (20:80, v/v) and a flow rate of 2 ml/min. In-vitro metabolic N-oxidation was achieved by incubating the parent drug, tinidazole, with rat liver homogenates fortified with cofactors at 37°C. HPLC analysis of blood and urine samples from healthy volunteer subjects who took a single oral dose of tinidazole showed the presence of an in-vivo N-oxidation metabolite of the drug. The identical physicochemical characteristics of the synthetic and biologically produced tinidazole /V-oxide strongly suggest that tinidazole, a tertiary amine drug, undergoes metabolic N-oxidation.