Hiroshima International University, Hiroshima, Japan.
Bodor Laboratories, Miami, Florida, USA.
Expert Opin Drug Metab Toxicol. 2021 May;17(5):555-580. doi: 10.1080/17425255.2021.1902986. Epub 2021 Apr 8.
: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.
: P-糖蛋白（P-gp）的表达向小肠远端增加，这意味着十二指肠是 P-gp 底物药物的优先吸收部位。亲脂性 P-gp 底物药物的口服生物利用度低且变化较大，但随富含脂类成分和胆汁的高脂肪餐增加，在十二指肠中增加。: 本文通过 PubMed 文献检索，综述了 P-gp 底物药物的吸收特性以及影响其溶解度和生物利用度的因素和口服剂型。从“弹簧和降落伞方法”的角度提供了一个概述，该方法可使亲脂性 P-gp 底物药物产生过饱和。: 由于溶解度低、优先吸收部位以及与 CYP3A4 的底物特异性重叠，以及肠道 P-gp 表达/功能的分散，P-gp 底物药物的口服生物利用度难以预测。为了获得低溶解度 P-gp 底物药物的高且稳定的口服生物利用度，优选对药物进行物理化学修饰以提高溶解度，或使用可在十二指肠中产生持久过饱和的口服剂型。特别是，可增加被动扩散和/或淋巴吸收的超饱和脂质给药系统是有效的，适用于许多低溶解度 P-gp 底物药物。
