Patients with diabetic mellitus tend to have a poor response to clopidogrel (Clop) due to reduced generation of active metabolite (Clop-AM). However, the underlying mechanism is not elucidated. A type 2 diabetic mellitus (T2DM) rat model was established by combining high-fat diet feeding and low-dose streptozotocin (STZ) injection. The reduced Clop-AM exposure was observed in T2DM rats after oral administration of Clop. However, in vitro liver microsomes incubated with Clop exhibited increased Clop-AM levels in T2DM rats due to a significant decrease in carboxylesterase (CES)1 expression and activity and a significant increase in the expression or activity of CYP1A2 and CYP3A . Interestingly, different from oral administration, the significantly increased C max of Clop-AM was observed in T2DM rats after intravenous injection, with no difference in AUC 0-t and t 1/2 values between the two strains. Meanwhile, in situ single -pass intestinal perfusion study showed lower absorption rate constant ( K a) and effective apparent permeability values ( P eff ) of Clop in T2DM rats than in control rats. It is explained by the increased expression or function of P-glycoprotein (P-gp) and pregnane X receptor (PXR) in duodenum and jejunum of T2DM rats. Moreover, the decreased Clop-AM level in T2DM rats was eliminated by the pretreatment of cyclosporin A , a P-gp inhibitor. It suggests that intestinal absorption, not hepatic metabolism is responsible for the reduced Clop-AM exposure in T2DM rats. P-gp might be the key factor causing the reduction of Clop absorption, consequently making less Clop available for Clop-AM formation.
Can Wu,Chunlu Wang,Yaoyao Zheng,Yaxin Zheng,Ziqi Liu,Keming Xu,Wenying Zhong
Cancerous cells exhibit overexpression of multiple enzymes in various cellular compartments. These enzymes are often undruggable, yet display unique advantages in regulating intracellular self-assembly and dis-assembly of small molecules for cancer targeting. Herein, a self-assembling molecule (LND-1p-ES) for carrier-free delivery of lonidamine specifically to cancerous cells is designed, where LND-1p-ES executes as both a drug and a carrier with combined benefits thereof. Under the precise regulation of phosphatase (ALP) and esterase (CES), LND-1p-ES is capable of self-assembling intracellularly in a spatiotemporal manner, to confer lonidamine-borne nanofibers with enhanced cellular uptake. These nanofibers also facilitate controlled drug release with the aid of cellular proteases. Taking advantages of overexpressing ALP and CES as well as proteases in cancerous cells, the LND-1p-ES formulation demonstrates enhanced potency and selectivity against melanoma cells A375 in vitro and in vivo. In comparison, none/single enzyme responsive compounds fail to show a similar potency or selectivity, further confirming the indispensable roles of these enzymes in the delivery system. Collectively, the research provides a viable strategy to utilize multiple enzymes in cancerous cells for regulation of intracellular self-assembly, which can be expanded to design smart soft materials responsive to multiple biologically relevant biomolecules for enhanced therapeutic efficacy.
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