Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions
Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug–drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertens...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-03-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/15/3/1020 |
| _version_ | 1827747994753040384 |
|---|---|
| author | Ruhul Kayesh Vishakha Tambe Chao Xu Wei Yue |
| author_facet | Ruhul Kayesh Vishakha Tambe Chao Xu Wei Yue |
| author_sort | Ruhul Kayesh |
| collection | DOAJ |
| description | Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug–drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). OATP1B1/1B3-related DDIs in humans have been reported for several CCBs. To date, the OATP1B1/1B3-mediated DDI potential of CCB nicardipine has not been assessed. The current study was designed to assess the OATP1B1- and OATP1B3-mediated DDI potential of nicardipine using the R-value model, following the US-FDA guidance. IC<sub>50</sub> values of nicardipine against OATP1B1 and OATP1B3 were determined in transporter-overexpressing human embryonic kidney 293 cells using [<sup>3</sup>H]-estradiol 17β-D-glucuronide and [<sup>3</sup>H]-cholecystokinin-8 as substrates, respectively, with or without nicardipine-preincubation in protein-free Hanks’ Balanced Salt Solution (HBSS) or in fetal bovine serum (FBS)-containing culture medium. Preincubation with nicardipine for 30 min in protein-free HBSS buffer produced lower IC<sub>50</sub> and higher R-values for both OATP1B1 and OATP1B3 compared to in FBS-containing medium, yielding IC<sub>50</sub> values of 0.98 and 1.63 µM and R-values of 1.4 and 1.3 for OATP1B1 and OATP1B3, respectively. The R-values were higher than the US-FDA cut-off value of 1.1, supporting that nicardipine has the potential to cause OATP1B1/3-mediated DDIs. Current studies provide insight into the consideration of optimal preincubation conditions when assessing the OATP1B1/3-mediated DDIs in vitro. |
| first_indexed | 2024-03-11T06:01:03Z |
| format | Article |
| id | doaj.art-3f3fb6529c904809a6e29d48eea395d5 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T06:01:03Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-3f3fb6529c904809a6e29d48eea395d52023-11-17T13:17:39ZengMDPI AGPharmaceutics1999-49232023-03-01153102010.3390/pharmaceutics15031020Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug InteractionsRuhul Kayesh0Vishakha Tambe1Chao Xu2Wei Yue3Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USADepartment of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USADepartment of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USAImpaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug–drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). OATP1B1/1B3-related DDIs in humans have been reported for several CCBs. To date, the OATP1B1/1B3-mediated DDI potential of CCB nicardipine has not been assessed. The current study was designed to assess the OATP1B1- and OATP1B3-mediated DDI potential of nicardipine using the R-value model, following the US-FDA guidance. IC<sub>50</sub> values of nicardipine against OATP1B1 and OATP1B3 were determined in transporter-overexpressing human embryonic kidney 293 cells using [<sup>3</sup>H]-estradiol 17β-D-glucuronide and [<sup>3</sup>H]-cholecystokinin-8 as substrates, respectively, with or without nicardipine-preincubation in protein-free Hanks’ Balanced Salt Solution (HBSS) or in fetal bovine serum (FBS)-containing culture medium. Preincubation with nicardipine for 30 min in protein-free HBSS buffer produced lower IC<sub>50</sub> and higher R-values for both OATP1B1 and OATP1B3 compared to in FBS-containing medium, yielding IC<sub>50</sub> values of 0.98 and 1.63 µM and R-values of 1.4 and 1.3 for OATP1B1 and OATP1B3, respectively. The R-values were higher than the US-FDA cut-off value of 1.1, supporting that nicardipine has the potential to cause OATP1B1/3-mediated DDIs. Current studies provide insight into the consideration of optimal preincubation conditions when assessing the OATP1B1/3-mediated DDIs in vitro.https://www.mdpi.com/1999-4923/15/3/1020drug–drug interactionsOATPpharmacokineticsdrug transporters |
| spellingShingle | Ruhul Kayesh Vishakha Tambe Chao Xu Wei Yue Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions Pharmaceutics drug–drug interactions OATP pharmacokinetics drug transporters |
| title | Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions |
| title_full | Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions |
| title_fullStr | Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions |
| title_full_unstemmed | Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions |
| title_short | Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions |
| title_sort | differential preincubation effects of nicardipine on oatp1b1 and oatp1b3 mediated transport in the presence and absence of protein implications in assessing oatp1b1 and oatp1b3 mediated drug drug interactions |
| topic | drug–drug interactions OATP pharmacokinetics drug transporters |
| url | https://www.mdpi.com/1999-4923/15/3/1020 |
| work_keys_str_mv | AT ruhulkayesh differentialpreincubationeffectsofnicardipineonoatp1b1andoatp1b3mediatedtransportinthepresenceandabsenceofproteinimplicationsinassessingoatp1b1andoatp1b3mediateddrugdruginteractions AT vishakhatambe differentialpreincubationeffectsofnicardipineonoatp1b1andoatp1b3mediatedtransportinthepresenceandabsenceofproteinimplicationsinassessingoatp1b1andoatp1b3mediateddrugdruginteractions AT chaoxu differentialpreincubationeffectsofnicardipineonoatp1b1andoatp1b3mediatedtransportinthepresenceandabsenceofproteinimplicationsinassessingoatp1b1andoatp1b3mediateddrugdruginteractions AT weiyue differentialpreincubationeffectsofnicardipineonoatp1b1andoatp1b3mediatedtransportinthepresenceandabsenceofproteinimplicationsinassessingoatp1b1andoatp1b3mediateddrugdruginteractions |