Bile acid transporter-mediated oral drug delivery

Abstract

Bile acids are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum at meals. Apical sodium-dependent bile acid transporter (ASBT), an ileal Na⁺-dependent transporter, plays the leading role of bile acid absorption into enterocytes, where bile acids are delivered to basolateral side by ileal bile acid binding protein (IBABP) and then released by organic solute transporter OSTα/β. The absorbed bile acids are delivered to the liver via portal vein. In this process called "enterohepatic recycling", only 5% of the bile acid pool (~3 g in human) is excreted in feces, indicating the large recycling capacity and high transport efficacy of ASBT-mediated absorption. Therefore, bile acid transporter-mediated oral drug delivery has been regarded as a feasible and potential strategy to improve the oral bioavailability. This review introduces the key factors in enterohepatic recycling, especially the mechanism of bile acid uptake by ASBT, and the development of bile acid-based oral drug delivery for ASBT-targeting, including bile acid-based prodrugs, bile acid/drug electrostatic complexation and bile acid-containing nanocarriers. Furthermore, the specific transport pathways of bile acid in enterocytes are described and the recent finding of lymphatic delivery of bile acid-containing nanocarriers is discussed.

Keywords: ASBT; Bile acid; Enterohepatic circulation; Lymphatic delivery; Oral drug delivery; Transporter.

Figure 1.

Enterohepatic recycling of bile acids. Bile acids are synthesized in the liver and stored in the gallbladder. At meals, bile acids are excreted to the duodenum for fat emulsification. In small intestine, most bile acids are reabsorbed in the ileum by apical sodium-dependent bile salt transporter (ASBT) and transported back to the liver via portal blood circulation. In this process, about 95% of bile acids are recycled to the liver, and only 5% (~0.5 g) is excreted, which is replenished by the newly synthesized bile acid in the liver. Reproduced, with permission, from reference [58].

Figure 2.

Common bile acid chemical structure and classification.

Figure 3.

Stages of dietary lipid absorption from intestinal lumen into villi, transporting though the enterocytes and collected by lacteals into systemic circulation. Reproduced, with permission, from reference [79].

Figure 4.

Distribution of ASBT after incubation with G40/CPN in SK-BR-3 cells for 3, 6 and 24 h. Green: ASBT, Red: G40/CPN, Blue: nuclei. Reproduced, with permission, from reference [93].

Figure 5.

The immunohistochemistry analysis of ASBT distribution in rats after LHe-tetraD treatment. ASBT was internalized from apical membrane to sub-apical compartment in rat ileum after treatment with LHe-tetraD in 1 h, and then gradually recycled to the apical membrane in 24 h. With LHe-tetraD absorption and ASBT uptake, IBABP expression simultaneously increased in 1 h and then decreased. Reproduced, with permission, from reference [92].

Figure 6.

Effect of EGFR2R-lytic hybrid peptide-TDCA-citric acid complex. (A) Measurement of antitumor effect of complex by monitoring tumor size in mice. The complex demonstrated higher tumor inhibition than cationic peptide and S-1 (5-FU oral formulation, positive control). (B) Tight junction opening effect of the complex in Caco-2 cell monolayers. Reproduced, with permission, from reference [126].

Figure 7.

EL-CSG design and its efficacy in oral absorption enhancement. Glycocholic acid was conjugated to CS and then coated on Ex-4 loaded liposomes. After oral administration, EL-CSG was mainly absorbed by ASBT-mediated intestinal uptake in small intestine, with 19.5% oral bioavailability compared with s.c. injection. Reproduced, with permission, from reference [143].

Figure 8.

(A–B) Tumor accumulation and antitumor activity of HDTA in KB tumor bearing mice. (C–D) Tumor accumulation and antitumor activity of HDTA4 and HTA3 in MDA-MB231 tumor bearing nude mice. (E) Tumor volume in in MDA-MB231 tumor bearing nude mice after HDTA4 and HTA3 treatment. (F) Schematic illustration of HDTA for oral delivery of DTX using bile acid transporter. Reproduced, with permission, from reference [152].