Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors.
The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72?h after a single 1.25-mg/m2 subcutaneous dose of 14C-omacetaxine in cancer patients.
High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification.
In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4′-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4′-desmethyl homoharringtonine (4′-DMHHT) was the most abundant metabolites.
Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.
Summary Eighteen patients entered this study of the efficacy of homoharringtonine (HHT) treatment in advanced squamous cell carcinoma of the head and neck (SCCHN). Seventeen eligible patients received at least one day of the first 5-day cycle of HHT (4.0 mg/m2/day) by continuous IV infusion. Cycles were scheduled to repeat every 28 days. The major severe toxicities encountered were hypotension and myelosuppression. There was one drug-related death. Fourteen patients were evaluable for response, and no patient exhibited an objective response to treatment with HHT.Abbreviations HHT
homoharringtonine
- SCCHN
squamous cell carcinoma of the head and neck
- BP
blood pressure
- HCT
hematocrit
- CBC
complete blood count
- WBC
white blood cell count 相似文献
Homoharringtonine (HHT) is a plant alkaloid with antileukemia activity that is currently being used for treatment of acute, chronic leukemias and MDS. In this study, we show that HHT can induce apoptosis in a variety of human myeloid leukemia cell lines (U937, HL-60, HEL, THP, and K562). U937 and HL60 cells undergo rapid apoptosis on treatment with HHT, as indicated by increased annexin V binding capacity, caspase-3 activation, and cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the expression of bax is upregulated during HHT-induced cell death, whereas the expression of bcl-2 is only slightly decreased. Importantly, treatment of primary leukemic cells, obtained from acute myeloid leukemia patients, resulted in rapid apoptosis. Thus, our data provide the mechanism of HHT and justify the use of HHT in the treatment of human myeloid leukemia. 相似文献