N-Hydroxyapiosporamide(N-hydap),a marine product derived from a sponge-associated fungus,has shown promising inhibitory effects on small cell lung cancer(SCLC).However,there is limited understanding of its metabolic p...N-Hydroxyapiosporamide(N-hydap),a marine product derived from a sponge-associated fungus,has shown promising inhibitory effects on small cell lung cancer(SCLC).However,there is limited understanding of its metabolic pathways and characteristics.This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s(CYPs)and UDP-glucuronosyltransferases(UGTs),as well as human/rat/mice microsomes,and also the pharmacokinetic properties by HPLC-MS/MS.Additionally,the cocktail probe method was used to investigate the potential to create drug-drug interactions(DDIs).N-Hydap was metabolically unstable in various microsomes after 1 h,with about 50%and 70%of it being eliminated by CYPs and UGTs,respectively.UGT1A3 was the main enzyme involved in glucuronidation(over 80%),making glucuronide the primary metabolite.Despite low bioavailability(0.024%),N-hydap exhibited a higher distribution in the lungs(26.26%),accounting for its efficacy against SCLC.Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity.Furthermore,N-hydap was found to affect the catalytic activity of drug metabolic enzymes(DMEs),particularly increasing the activity of UGT1A3,suggesting potential for DDIs.Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy,toxicity,and potential for DDIs.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82274002,42376124)Marine Economy Development Project of Guangdong Province(GDNRC[2021]52)+1 种基金Hainan Provincial Natural Science Foundation of China(823CXTD393)Key-Area Research and Development Program of Guangdong Province(2023B1111050008)。
文摘N-Hydroxyapiosporamide(N-hydap),a marine product derived from a sponge-associated fungus,has shown promising inhibitory effects on small cell lung cancer(SCLC).However,there is limited understanding of its metabolic pathways and characteristics.This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s(CYPs)and UDP-glucuronosyltransferases(UGTs),as well as human/rat/mice microsomes,and also the pharmacokinetic properties by HPLC-MS/MS.Additionally,the cocktail probe method was used to investigate the potential to create drug-drug interactions(DDIs).N-Hydap was metabolically unstable in various microsomes after 1 h,with about 50%and 70%of it being eliminated by CYPs and UGTs,respectively.UGT1A3 was the main enzyme involved in glucuronidation(over 80%),making glucuronide the primary metabolite.Despite low bioavailability(0.024%),N-hydap exhibited a higher distribution in the lungs(26.26%),accounting for its efficacy against SCLC.Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity.Furthermore,N-hydap was found to affect the catalytic activity of drug metabolic enzymes(DMEs),particularly increasing the activity of UGT1A3,suggesting potential for DDIs.Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy,toxicity,and potential for DDIs.
