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Abstract Plasma 4β‐hydroxycholesterol (OHC) has drawn attention as an endogenous substrate indicating CYP3A activity. Plasma 4β‐OHC is produced by hydroxylation by CYP3A4 and CYP3A5 and by cholesterol autoxidation. Plasma 4α‐OHC is produced by cholesterol autoxidation and not affected by CYP3A activity. This study aimed to evaluate the usefulness of plasma 4β‐OHC concentration minus plasma 4α‐OHC concentration (4β‐OHC–4α‐OHC) compared with plasma 4β‐OHC concentration and 4β‐OHC/total cholesterol (TC) ratio in cross‐sectional evaluation of CYP3A activity. Four hundred sixteen general adults were divided into 191 CYP3A5*1 carriers and 225 non‐carriers. Twenty‐six patients with chronic kidney disease (CKD) with CYP3A5*1 allele were divided into 14 with CKD stage 3 and 12 with stage 4–5D. Area under the receiver operating characteristic curve (AUC) for the three indices were evaluated for predicting presence or absence of CYP3A5*1 allele in general adults, and for predicting CKD stage 3 or stage 4–5D in patients with CKD. There was no significant difference between AUC of 4β‐OHC–4α‐OHC and AUC of plasma 4β‐OHC concentration in general adults and in patients with CKD. AUC of 4β‐OHC–4α‐OHC was significantly smaller than that of 4β‐OHC/TC ratio in general adults (p = 0.025), but the two indices did not differ in patients with CKD. In conclusion, in the present cross‐sectional evaluation of CYP3A activity in general adults and in patients with CKD with CYP3A5*1 allele, the usefulness of 4β‐OHC–4α‐OHC was not different from plasma 4β‐OHC concentration or 4β‐OHC/TC ratio. However, because of the limitations in study design and subject selection of this research, these findings require verification in further studies.

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.

Abstract Plasma coproporphyrin‐I (CP‐I) concentration is used as a sensitive and selective endogenous probe for phenotyping organic anion transporting polypeptides 1B (OATP1B) activity in many studies. CP‐I is produced in the process of heme synthesis, but the relationship between plasma CP‐I concentrations and heme synthesis activity is unknown. In this study, we evaluated the relationship between plasma CP‐I concentration and hemoglobin level as a biomarker of heme synthesis activity. The data of 391 subjects selected from the Japanese general population were analyzed. One hundred twenty‐six participants had OATP1B1*15 allele, 11 of whom were homozygous (OATP1B1*15/*15). Multiple regression analysis identified hemoglobin level as an independent variable associated with plasma CP‐I concentration (p