Factors Influencing Plasma Coproporphyrin‐I Concentration as Biomarker of OATP1B Activity in Patients With Rheumatoid Arthritis

Abstract

Organic anion transporting polypeptides (OATPs) 1B are drug transporters mainly expressed in the sinusoidal membrane. In previous reports, genetic factor, 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid (CMPF), which is one of the uremic toxins, inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) decreased OATP1B1 activity in vitro, but in vivo effects of these factors have not been elucidated. Plasma coproporphyrin‐I (CP‐I) is spotlighted as a highly accurate endogenous substrate of OATP1B. This study focused on patients with rheumatoid arthritis (RA) and evaluated the influence of several factors comprising gene polymorphisms, uremic toxins, and inflammatory cytokines on OATP1B activity using plasma CP‐I concentration. Thirty‐seven outpatients with RA who satisfied the selection criteria were analyzed at the time of recruitment (baseline) and at the next visit. OATP1B1*15 carriers tended to have higher CP‐I concentration compared with noncarriers. Plasma CP‐I correlated positively with CMPF concentration, but did not correlate with IL‐6 or TNF‐α concentration. Multiple logistic regression analysis by stepwise selection identified plasma CMPF concentration and OATP1B1*15 allele as significant factors independently affecting plasma CP‐I concentration at baseline and at the next visit, respectively. In conclusion, the present results suggest that inflammatory cytokines do not have clinically significant effects on OATP1B activity, whereas the effects of genetic polymorphisms and uremic toxins should be considered.

Positive correlation between organic anion transporter 1B function indicated by plasma concentration of coproporphyrin‐I and blood concentration of cyclosporin A in real‐world patients

“…However, the concentrations of exposure were very high: 10 ng/mL of IL‐6 and 100 ng/mL of TNF‐α, which are rarely observed in human plasma. Further, in our previous study in patients with RA, there was no correlation between plasma CP‐I concentration and plasma IL‐6 or TNF‐α concentration 17 . Multiple regression analysis in the present study found that the contribution of CRP concentration to plasma CP‐I concentration was less than that of blood CyA concentration.…”

“…CMPF is one of the uraemic toxins that accumulate in patients with CKD. Our previous studies in healthy volunteers and patients with CKD 16 or RA 17 uncovered a positive correlation between plasma CP‐I and CMPF concentrations. Additionally, multivariate analysis identified plasma CMPF concentration and OATP1B polymorphism as significant factors affecting plasma CP‐I concentration 17 .…”

“…16 Moreover, our previous research identified plasma CMPF concentration and genetic background as significant factors affecting plasma CP-I concentration in rheumatoid arthritis (RA) patients. 17 CyA, a calcineurin inhibitor, has been reported to inhibit OATP1B activity in vivo and in vitro. 10 Shen et al 12 demonstrated that oral administration of CyA at 100 mg/kg increased the AUC of CP-I by 2.6-fold in animals.…”

Physiologically‐based pharmacokinetic model‐based translation of OATP1B‐mediated drug–drug interactions from coproporphyrin I to probe drugs

“…The endogenous substrates of OATP1B, such as coproporphyrin I (CP‐I), is considered as functional biomarkers to detect changes of OATP1B activity by OATP1B inhibitor drugs, when the administration of probe drugs is not practical 8,9 . CP‐I has also been used to investigate genetic variations in OATP1B1*15 10–12 and the effect of disease conditions on OATP1B activities 13,14 . Significant effect of OATP1B1 genotypes on the plasma CP‐I concentrations supports major contribution of OATP1B1 to the hepatic uptake of CP‐I.…”

“… 8 , 9 CP‐I has also been used to investigate genetic variations in OATP1B1*15 10 , 11 , 12 and the effect of disease conditions on OATP1B activities. 13 , 14 Significant effect of OATP1B1 genotypes on the plasma CP‐I concentrations supports major contribution of OATP1B1 to the hepatic uptake of CP‐I. Likewise, after administration of an inhibitor of OATP1B1/1B3, the plasma concentration of CP‐I displayed a transient increase, and the magnitude of change in the maximum plasma concentrations (C max ) and the area under the plasma concentration time curve (AUC) depend on the magnitude of OATP1B inhibition during the study.…”