High-fat diets enhance and delay ursodeoxycholic acid absorption but elevate circulating hydrophobic bile salts

Abstract

Background: Ursodeoxycholic acid (UDCA) is a natural drug essential for the treatment of cholestatic liver diseases. The food effects on the absorption of UDCA and the disposition of circulating bile salts remain unclear despite its widespread global uses. This study aims to investigate the effects of high-fat (HF) diets on the pharmacokinetics of UDCA and disclose how the circulated bile salts were simultaneously perturbed. Methods: After an overnight fast, a cohort of 36 healthy subjects received a single oral dose (500 mg) of UDCA capsules, and another cohort of 31 healthy subjects received the same dose after consuming a 900 kcal HF meal. Blood samples were collected from 48 h pre-dose up to 72 h post-dose for pharmacokinetic assessment and bile acid profiling analysis. Results: The HF diets significantly delayed the absorption of UDCA, with the T_max of UDCA and its major metabolite, glycoursodeoxycholic acid (GUDCA), changing from 3.3 h and 8.0 h in the fasting study to 4.5 h and 10.0 h in the fed study, respectively. The HF diets did not alter the C_max of UDCA and GUDCA but immediately led to a sharp increase in the plasma levels of endogenous bile salts including those hydrophobic ones. The AUC_0-72h of UDCA significantly increased from 25.4 μg h/mL in the fasting study to 30.8 μg h/mL in the fed study, while the AUC_0-72h of GUDCA showed no difference in both studies. As a result, the C_max of total UDCA (the sum of UDCA, GUDCA, and TUDCA) showed a significant elevation, while the AUC_0-72h of total UDCA showed a slight increase without significance in the fed study compared to the fasting study. Conclusion: The HF diets delay UDCA absorption due to the extension of gastric empty time. Although UDCA absorption was slightly enhanced by the HF diets, the beneficial effect may be limited in consideration of the simultaneous elevation of circulating hydrophobic bile salts.

Keywords: bile acids; bile salts; food effect; glycoursodeoxycholic acid; pharmacokinetics; ursodeoxycholic acid.

FIGURE 1

Metabolism and disposition of exogenous oral UDCA are intercrossed into the metabolic pathways of endogenous bile salts. Abbreviations: 3-HSDH, 3-hydroxysteroid dehydrogenase; 7-HSDH, 7-hydroxysteroid dehydrogenase; 12-epiDCA, 3α, 12β-dihydroxy-5β-cholan-24-oic acid; ASBT, apical sodium-dependent bile acid transporter; Bais, bile acid-inducible genes; BSEP, bile salt export pump; BSH, bile salt hydrolase; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP3A, cytochrome P450 3A; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; GUDCA, glycoursodeoxycholic acid; HDCA, hyodeoxycholic acid; isoUDCA, isoursodeoxycholic acid; LCA, lithocholic acid; NTCP, sodium taurocholate co-transporting polypeptide; OATP, organic anion transporting polypeptide; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; and UDCA, ursodeoxycholic acid.

FIGURE 2

Average plasma concentration–time curves of UDCA, GUDCA, and TUDCA in the fasting study and the fed study (A) and the three absorption types of subjects categorized according to the time to reach the maximum concentration of UDCA (B). The data are shown as the mean ± SEM. Abbreviations: UDCA, ursodeoxycholic acid; GUDCA, glycoursodeoxycholic acid; and TUDCA, tauroursodeoxycholic acid.

FIGURE 3

Average plasma concentration–time curves of endogenous bile salts after oral UDCA administration in the fasting study and the fed study. The data are shown as the mean ± SEM. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; GUDCA, glycoursodeoxycholic acid; isoUDCA, isoursodeoxycholic acid; LCA, lithocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; UDCA, ursodeoxycholic acid; 12-epiDCA, 3α, 12β-dihydroxy-5β-cholan-24-oic acid; isoDCA, isodeoxycholic acid; and GαHCA, 7α-glycohyocholic acid.

FIGURE 4

Molar percentages of circulating bile salts calculated according to AUC_-48-0h, AUC_0–4h, AUC_4–12h, and AUC_12–72h of 16 bile salts. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; GUDCA, glycoursodeoxycholic acid; isoUDCA, isoursodeoxycholic acid; LCA, lithocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; UDCA, ursodeoxycholic acid; 12-epiDCA, 3α, 12β-dihydroxy-5β-cholan-24-oic acid; isoDCA, isodeoxycholic acid; and GαHCA, 7α-glycohyocholic acid.