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Further Evaluation of Coproporphyrins as Clinical Endogenous Markers for OATP1B
Author(s) -
Feng Sheng,
Bo Qingyan,
Coleman Hugh A.,
Charoin Jean Eric,
Zhu Mingfen,
Xiao Jim,
Jin Yuyan
Publication year - 2021
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1817
Subject(s) - pitavastatin , confidence interval , urine , medicine , endogeny , pharmacokinetics , pharmacology , organic anion transporting polypeptide , plasma concentration , chemistry , endocrinology , gastroenterology , transporter , biochemistry , statin , gene
Coproporphyrins (CP‐I and CP‐III) in plasma are considered potential markers for assessing liver organic anion‐transporting polypeptide transporter OATP1B activity and monitoring OATP1B‐mediated drug‐drug interactions (DDIs) in clinical settings. However, the effect of altered renal clearance (CL renal ) on CP‐I and CP‐III plasma exposure has rarely been examined. Therefore, the purpose of this study is to further evaluate CP‐I and CP‐III as clinical endogenous markers for OATP1B activity and to investigate the impact of CL renal on DDI assessments for the first time. In this study, 18 healthy participants were recruited to receive RO7049389 (a potential inhibitor of OATP1B) 800 mg twice daily for 6 days and a single dose of pitavastatin (a probe drug of OATP1B) before and after RO7049389 treatment. Plasma concentrations of pitavastatin, CP I, CP III, and the amounts of CP‐I and CP‐III excreted in urine were measured. Seventeen healthy participants completed the study. After multiple doses of RO7049389, the area under the plasma concentration–time curve from time 0 to 12 hours of pitavastatin increased 1.95‐fold (90% confidence interval [CI], 1.58‐2.41), while for CP‐I and CP‐III it increased 3.00‐fold (90%CI, 2.35‐3.82) and 2.84‐fold (90%CI, 2.22‐3.65), respectively. Concurrently, the CL renal of CP‐I decreased by 31% (90%CI, 23%‐39%), and that of CP‐III decreased by 70% (90%CI, 61%‐77%). In conclusion, CP‐I and CP‐III in plasma display the potential to be applied as endogenous markers for the evaluation of OATP1B inhibition in clinical trials. While renal transporters contribute significantly to the CL renal of CP‐III, it would be better to investigate the impact of the CL renal on plasma exposure of CP‐III during clinical DDI assessments.