Bile Acid-Drug Interaction via Organic Anion-Transporting Polypeptide 4C1 Is a Potential Mechanism of Altered Pharmacokinetics of Renally Excreted Drugs

Abstract

Patients with liver diseases not only experience the adverse effects of liver-metabolized drugs, but also the unexpected adverse effects of renally excreted drugs. Bile acids alter the expression of renal drug transporters, however, the direct effects of bile acids on drug transport remain unknown. Renal drug transporter organic anion-transporting polypeptide 4C1 (OATP4C1) was reported to be inhibited by chenodeoxycholic acid. Therefore, we predicted that the inhibition of OATP4C1-mediated transport by bile acids might be a potential mechanism for the altered pharmacokinetics of renally excreted drugs. We screened 45 types of bile acids and calculated the IC50, Ki values, and bile acid−drug interaction (BDI) indices of bile acids whose inhibitory effect on OATP4C1 was >50%. From the screening results, lithocholic acid (LCA), glycine-conjugated lithocholic acid (GLCA), and taurine-conjugated lithocholic acid (TLCA) were newly identified as inhibitors of OATP4C1. Since the BDI index of LCA was 0.278, LCA is likely to inhibit OATP4C1-mediated transport in clinical settings. Our findings suggest that dose adjustment of renally excreted drugs may be required in patients with renal failure as well as in patients with hepatic failure. We believe that our findings provide essential information for drug development and safe drug treatment in clinics.

Keywords: OATP4C1; bile acids; bile acid–drug interaction; lithocholic acid; liver disease; renally excreted drugs.

Figure 1

Chemical structures of (A) unconjugated, glycine-conjugated, and taurine-conjugated bile acids, (B) bile acid 3-sulfates, and (C) bile acid 3-glucuronides.

Figure 2

Inhibitory effect of 45 bile acids on OATP4C1-mediated T₃ transport. (A) unconjugated, glycine-conjugated, and taurine-conjugated bile acids, (B) bile acid 3-sulfates, and (C) bile acid 3-glucuronides. The T₃ concentration was 1 µM and cells were incubated for 10 min at 37 °C. The bile acid concentrations were 50 µM for CA-3S, LCA-3S, TDCA-3S, LCA-3GlcA, and GLCA-3GlcA, and 100 µM for the other 40 types of bile acids. The OATP4C1-mediated transport was calculated by subtracting the nonspecific uptake of T₃ by the mock cells from the total cellular uptake by the OATP4C1-expressing cells. Each column and bar represent the mean ± standard error of the mean (n = 3). The data are shown as the percentages of transport relative to the control. An asterisk indicates a significant difference from the control by one-way analysis of variance (ANOVA) followed by Tukey’s test (p < 0.05).

Figure 3

Concentration dependence of the inhibitory effect of the bile acids on the OATP4C1-mediated T₃ transport. (A) LCA, (B) GLCA, and (C) TLCA. The T₃ concentration was 1 µM and the cells were incubated for 10 min at 37 °C. The bile acid concentrations were 0, 0.3, 1, 3, 10, 30, and 100 µM for LCA and GLCA, and 0, 1, 3, 10, 30, 100, and 200 µM for TLCA. The OATP4C1-mediated transport was calculated by subtracting the nonspecific uptake of T₃ by the mock cells from the total cellular uptake by the OATP4C1-expressing cells. Each point and bar represent the mean ± standard error of the mean (n = 3). The data are shown as the percentages of transport relative to the control. The dotted lines represent the fitted line obtained by nonlinear least squares regression analysis.

Figure 4

Effect of (A) unconjugated, glycine-conjugated, and taurine-conjugated bile acids, (B) bile acid 3-sulfates, and (C) bile acid 3-glucuronides on cellular viability. The bile acid concentrations were 50 µM for CA-3S, LCA-3S, TDCA-3S, LCA-3GlcA, and GLCA-3GlcA, and 100 µM for the other 40 types of bile acids. The OATP4C1-expressing cells were incubated for 10 min at 37 °C. After a 3 h color reaction, the absorbance was measured at 450 nm. Data are shown as mean ± standard error of the mean (n = 5). Data are presented as the percentages of cell viability obtained from the control.

Figure 5

Hypothetical scheme of the “bile acid–uremic toxin negative spiral”. OATP4C1 inhibition by bile acids causes the accumulation of uremic toxins, which may inhibit the bile acid uptake into hepatocytes via NTCP and OATPs. Further accumulation of uremic toxins and bile acids may be induced by the inhibition of OATP4C1 and hepatic bile acid transporters.