Relationship of plasma 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentration with OATP1B activity in patients with chronic kidney disease

Abstract

Organic anion-transporting polypeptides (OATP)1B are drug transporters mainly expressed in the sinusoidal membrane. Many studies have suggested that OATP1B activity is affected by genetic factor, the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Coproporphyrin-I (CP-I) is spotlighted as a highly accurate endogenous substrate of OATP1B. We previously reported a positive correlation between plasma CMPF and CP-I concentrations in patients with chronic kidney disease (CKD). The present study evaluated the impact of genetic polymorphisms, CMPF, IL-6, TNF-α, and estimated glomerular filtration rate (eGFR) on individual differences in OATP1B activity in patients with CKD. Seventy-three patients with CKD who received kidney transplant at least 3 months earlier were analyzed. Plasma CP-I concentration was higher in OATP1B1*15 carriers than in non-carriers. In all patients, CP-I did not correlate significantly with CMPF, IL-6, TNF-α, or eGFR. However, when the dataset was cut off at CMPF concentration of 8 and 7 μg/mL, 4 μg/mL, 3 μg/mL or 2 μg/mL, CMPF correlated positively with CP-I, and correlation coefficient tended to be higher as plasma CMPF concentration was lower. In conclusion, OATP1B1*15 impacted OATP1B activity in patients with CKD, but IL-6 and TNF-α did not. However, the impact of CMPF on OATP1B activity was limited to low CMPF concentrations, and the effect could be saturated at high concentrations. When prescribing an OATP1B substrate drug for patients with CKD, the OATP1B1*15 carrier status and plasma CMPF concentration may need to be considered to decide the dose regimen.

FIGURE 1

(a) Comparison of plasma (a) CP‐I and (b) CMPF concentrations between OATP1B1*15 carriers and non‐carriers. Plasma CP‐I and CMPF concentrations were analyzed by t‐test. CP‐I, coproporphyrin‐I; CMPF, 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid.

FIGURE 2

Correlation of plasma CP‐I concentration with (a) CMPF, (b) IL‐6, (c) TNF‐α, and (d) eGFR. All correlation analyses were conducted using Spearman rank correlation test. CP‐I, coproporphyrin‐I; CMPF, 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid; eGFR, estimated glomerular filtration rate; IL‐6, interleukin‐6; TNF, tumor necrosis factor.

FIGURE 3

Correlation between plasma CP‐I and CMPF concentrations when the dataset was cut off at plasma CMPF concentration of (a) 11 μg/mL, (b) 10 and 9 μg/mL, (c) 8 and 7 μg/mL, (d) 6 and 5 μg/mL, (e) 4 μg/mL, (f) 3 μg/mL, or (g) 2 μg/mL. Correlation was tested using Spearman rank correlation coefficient. CP‐I, coproporphyrin‐I; CMPF, 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid.

FIGURE 4

Correlation between plasma CP‐I concentration and eGFR when the dataset was cut off at plasma CMPF concentration of (a) 11 μg/mL, (b) 10 and 9 μg/mL, (c) 8 and 7 μg/mL, (d) 6 and 5 μg/mL, (e) 4 μg/mL, (f) 3 μg/mL, or (g) 2 μg/mL. Correlation was tested using Spearman rank correlation coefficient. CP‐I, coproporphyrin‐I; eGFR, estimated glomerular filtration rate.