Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug–Drug Interaction and Associated Biomarker Levels in Healthy Volunteers

Autor: Sook Wah Yee, Marilyn M. Giacomini, Hong Shen, W. Griffith Humphreys, Howard Horng, William Brian, Yurong Lai, Deanna L. Kroetz, Kathleen M. Giacomini
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Clinical and Translational Science, Vol 12, Iss 4, Pp 388-399 (2019)
Druh dokumentu: article
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.12625
Popis: Understanding transporter‐mediated drug–drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)‐I, and CP‐III as clinical biomarkers for evaluating organic anion‐transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c.521T>C (OATP1B1‐Val174Ala) on the extent of interaction between cyclosporin A (CsA) and pravastatin, and associated endogenous biomarkers of the transporter (HDA, TDA, CP‐I, and CP‐III), in 20 healthy volunteers. The results show that the levels of each clinical biomarker and pravastatin were significantly increased in plasma samples of the volunteers following administration of pravastatin plus CsA compared with pravastatin plus placebo. The overall fold change in the area under the concentration–time curve (AUC) and maximum plasma concentration (Cmax) was similar among the four biomarkers (1.8–2.5‐fold, paired t‐test P value C genotype is significantly associated with CP‐I but not CP‐III levels. Overall, these results suggest that OATP1B1 genotype can modulate the effects of CsA on biomarker levels; the extent of modulation differs among the biomarkers.
Databáze: Directory of Open Access Journals
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