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Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans

It was recently reported that the C(max) and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions bet...

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Autores principales: Bae, Soo Hyeon, Park, Wan-Su, Han, Seunghoon, Park, Gab-jin, Lee, Jongtae, Hong, Taegon, Jeon, Sangil, Yim, Dong-Seok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Korean Physiological Society and The Korean Society of Pharmacology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928345/
https://www.ncbi.nlm.nih.gov/pubmed/29719454
http://dx.doi.org/10.4196/kjpp.2018.22.3.321
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author Bae, Soo Hyeon
Park, Wan-Su
Han, Seunghoon
Park, Gab-jin
Lee, Jongtae
Hong, Taegon
Jeon, Sangil
Yim, Dong-Seok
author_facet Bae, Soo Hyeon
Park, Wan-Su
Han, Seunghoon
Park, Gab-jin
Lee, Jongtae
Hong, Taegon
Jeon, Sangil
Yim, Dong-Seok
author_sort Bae, Soo Hyeon
collection PubMed
description It was recently reported that the C(max) and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan–rosuvastatin case, simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the T(max) changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (C(maxI)/C(max): 2.01, AUC(I)/AUC:1.18, T(max): 5 h → 0.75 h). In the next case of cyclosporine–rosuvastatin, the simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CL(int,BCRP,intestine) of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin–telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin–cyclosporine interaction).
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spelling pubmed-59283452018-05-01 Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans Bae, Soo Hyeon Park, Wan-Su Han, Seunghoon Park, Gab-jin Lee, Jongtae Hong, Taegon Jeon, Sangil Yim, Dong-Seok Korean J Physiol Pharmacol Original Article It was recently reported that the C(max) and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan–rosuvastatin case, simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the T(max) changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (C(maxI)/C(max): 2.01, AUC(I)/AUC:1.18, T(max): 5 h → 0.75 h). In the next case of cyclosporine–rosuvastatin, the simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CL(int,BCRP,intestine) of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin–telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin–cyclosporine interaction). The Korean Physiological Society and The Korean Society of Pharmacology 2018-05 2018-04-25 /pmc/articles/PMC5928345/ /pubmed/29719454 http://dx.doi.org/10.4196/kjpp.2018.22.3.321 Text en Copyright © Korean J Physiol Pharmacol http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Bae, Soo Hyeon
Park, Wan-Su
Han, Seunghoon
Park, Gab-jin
Lee, Jongtae
Hong, Taegon
Jeon, Sangil
Yim, Dong-Seok
Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans
title Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans
title_full Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans
title_fullStr Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans
title_full_unstemmed Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans
title_short Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans
title_sort physiologically-based pharmacokinetic predictions of intestinal bcrp-mediated drug interactions of rosuvastatin in koreans
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928345/
https://www.ncbi.nlm.nih.gov/pubmed/29719454
http://dx.doi.org/10.4196/kjpp.2018.22.3.321
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