Nitazoxanide: pharmacokinetics and metabolism in man

OBJECTIVES: Nitazoxanide (N), a new broad-spectrum parasiticidal agent, is rapidly deacetylated to tizoxanide (T). The objective of the study was to determine if metabolites other than T are present in the plasma and excreted after single dose oral administration of radiocarbon-labelled N in healthy subjects. METHODS: Six healthy volunteers received a single 500 mg oral dose of N labelled with 2.92 MBq radiocarbon. The radioactivity in blood, plasma, urine, feces and expired air was monitored at scheduled intervals for up to 10 days. Selected samples were assayed by HPLC for T and submitted to metabolite identification by mass spectrometry. In vitro experiments were also conducted (incubation with animal and human microsomes, deacetylation kinetics). Plasma and bile samples obtained in a patient treated with N for sporozoal infection were also assayed for T. RESULTS: Elimination of radiocarbon occurred both in the urine (31.5% of the dose on average) and in the feces (66.2% on average). T and T-glucuronide contributed 15% of total urine radioactivity. N was found to deacetylate extremely rapidly to T in plasma (half-life of about 6 minutes at 37 degrees C) as well as in presence of liver microsomes. T was the only species obtained by incubation with human microsomes while rat microsomes yielded hydroxylated T in addition. The main species identified in human plasma, urine and bile was T-glucuronide, the identification of which was confirmed by comparison with an authentic sample. No species other than T was detected in feces, indicating intensive intestinal deconjugation, while radioactivity and absorbance detectors showed largely unresolved clusters.