No abstract

Coproporphyrin-I (CP-I) in plasma is a sensitive and specific endogenous probe for phenotyping organic anion transporting polypeptides 1B (OATP1B, encoded by SLCO1B). A few small-scale studies suggested that plasma CP-I concentration is affected by OATP1B1 polymorphism, but detailed studies are lacking. In this large-scale study, we measured plasma CP-I concentrations in 391 subjects from the Japanese general population, and evaluated the relationship between plasma CP-I concentrations and OATP1B1 polymorphisms to further assess the utility of plasma CP-I concentrations as an endogenous OATP1B probe. Plasma CP-I concentrations were 0.45 ± 0.12, 0.47 ± 0.16, 0.47 ± 0.20, 0.50 ± 0.15, 0.54 ± 0.14, and 0.74 ± 0.31 ng/mL in participants with OATP1B1*1b/*1b (n = 103), *1a/*1b (n = 122), *1a/*1a (n = 40), *1b/*15 (n = 74), *1a/*15 (n = 41), and *15/*15 (n = 11), respectively, showing an ascending rank order with significant difference (P < 0.0001). Post hoc analysis revealed significant increases in plasma CP-I concentration in OATP1B1*1b/*15 (P = 0.036), *1a/*15 (P = 0.0005), and *15/*15 (P = 0.0003) groups compared with the OATP1B1*1b/*1b group. There was no significant difference among OATP1B genotypes in plasma concentration of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, a uremic toxin reported to decrease OATP1B activity in vivo. These findings confirm the utility of plasma CP-I concentrations as an endogenous biomarker for phenotyping of OATP1B activity. Plasma CP-I concentration is potentially useful for the study of drug-drug interactions via OATP1B or individual dose adjustment of OATP1B substrates. Drug transporters are localized at cell membranes and involved in drug transport in various tissues such as the liver, kidneys, gastrointestinal tract, and brain endothelium. Organic anion transporting polypeptides 1B (OATP1B, encoded by SLCO1B) is a hepatic uptake transporter that substantially affect pharmacokinetics of some drugs, such as hydroxymethylglutaryl (HMG)-CoA reductase inhibitors and some anti-hepatitis C virus drugs. 1-6 In vivo OATP1B activity has large interindividual variability and is affected by environmental, physiologic, and genetic factors. For example, OATP inhibitors, such as rifampicin and cyclosporin A, inhibit OATP1B activity and increase plasma concentrations

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AimsIndoxyl sulfate and parathyroid hormone (PTH), which accumulate in chronic kidney disease (CKD), have been reported to reduce cytochrome P450(CYP)3A activity. Homozygotes of the CYP3A5*3 allele have reduced CYP3A5 activity compared to carriers of at least one CYP3A5*1 allele. 4β‐hydroxycholesterol (4β‐OHC) has been established as an endogenous substrate reflecting CYP3A activity. 4β‐OHC is produced through hydroxylation by CYP3A4 and CYP3A5 and by autoxidation of cholesterol, whereas 4α‐hydroxycholesterol (4α‐OHC) is produced solely by autoxidation of cholesterol. This study focused on CKD patients and evaluated the effects of plasma indoxyl sulfate and intact‐PTH concentrations on plasma 4β‐OHC concentration, 4β‐OHC/total cholesterol ratio, and 4β‐OHC – 4α‐OHC, with consideration of the influence of CYP3A5 polymorphism.MethodsSixty‐three CKD patients were analyzed and divided into CYP3A5 carrier group (N = 26) and non‐carrier group (N = 37).ResultsPlasma indoxyl sulfate significantly correlated inversely with 4β‐OHC concentration and with 4β‐OHC – 4α‐OHC in both the CYP3A5*1 carrier group (r = ‐0.42, p = 0.034; r = ‐0.39, p = 0.050, respectively) and the non‐carrier group (r = ‐0.45, p = 0.0054; r = ‐0.39, p = 0.019, respectively). However, multiple regression analysis did not identify plasma indoxyl sulfate concentration as a significant independent factor associated with any of the CYP3A activity indices. There was no significant correlation between plasma intact‐PTH concentration and any of the CYP3A activity indices.ConclusionThe present results suggest that plasma indoxyl sulfate and intact‐PTH concentrations do not have clinically significant effects on CYP3A activity in patients with CKD.

Aims Cyclosporin A (CyA) has potent inhibitory activity on organic anion transporting polypeptide 1B (OATP1B), causing drug–drug interactions with its substrate drugs. 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropionate (CMPF), a uraemic toxin, has also been suggested to inhibit OATP1B activity. Recent study has identified coproporphyrin‐I (CP‐I) as a specific endogenous substrate for OATP1B, which is useful to indicate OATP1B activity. We investigated the relationship of CP‐I with CyA and CMPF concentrations in patients taking CyA. Methods In total, 121 blood samples from 74 patients who took CyA and underwent routine therapeutic drug monitoring were divided into trough and peak samples. Results CyA and CP‐I concentrations were significantly higher in peak samples than in trough samples. A positive correlation between CP‐I and CyA concentrations was found in all samples and in trough and peak samples, while no correlation was observed between CP‐I and CMPF concentrations. Multiple regression analysis identified CyA and C‐reactive protein concentrations as independent factors affecting CP‐I concentration, with blood CyA concentration having markedly greater contribution to plasma CP‐I concentration. Conclusion The present study suggests that CyA inhibits OATP1B activity in a concentration‐dependent manner in clinical setting, and that dose adjustment of OATP1B substrate drugs coadministered with CyA according to plasma CMPF concentration may not be necessary.