Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1783319225510658048 |
---|---|
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). |
format | Online Article Text |
id | pubmed-5928345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Korean Physiological Society and The Korean Society of Pharmacology |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT baesoohyeon physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans AT parkwansu physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans AT hanseunghoon physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans AT parkgabjin physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans AT leejongtae physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans AT hongtaegon physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans AT jeonsangil physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans AT yimdongseok physiologicallybasedpharmacokineticpredictionsofintestinalbcrpmediateddruginteractionsofrosuvastatininkoreans |