Clinical studies, phase active metabolites

In a phase I study in patients with refractory solid tumours or lymphomas, ciclosporin 5 to 10 mg/kg was given as a 6-hour infusion beginning 3 hours before administration of irinotecan (initial dose 25 mg/m increased to 72 mg/m weekly). Ciclosporin increased the AUC of SN-38 (the active metabolite of irinotecan) by 23 to 630% and reduced irinotecan clearance by 39 to 64%, when compared with historical controls. The effects of ciclosporin on irinotecan may be due to inhibition of irinotecan-and SN-38-related biliary transporters, and this suggestion is supported by a study in Further clinical studies are needed to assess the effects of ciclosporin on the antitumour response and toxicity of irinotecan. 

ARQ 501 is a fully synthetic version of B-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b] pyran-5,6-dione) and has shown promising anticancer activity in multiple Phase II clinical trials. Recently, we disclosed the identification and characterization of the phase I metabolites of ARQ 501 from human blood. In continuation of our studies on the metabolism of ARQ 501, we studied the phase II metabolites in vivo. The sulfate and glucuronidate conjugates were identified as the two major metabolites formed in vivo. In this presentation, we will discuss the synthesis and structural elucidation of these sulfate and glucuronidate conjugates of ARQ 501. 

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