Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds
Renal impairment (RI) is a highly prevalent disease which can alter the pharmacokinetics (PK) of xenobiotics, including those that are predominately metabolized. The expression and activity of drug metabolizing enzymes (DMEs) and protein binding of compounds has been demonstrated to be affected in R...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-03-01
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| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1999-4923/11/3/105 |
| _version_ | 1828154969013878784 |
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| author | Kristin E. Follman Marilyn E. Morris |
| author_facet | Kristin E. Follman Marilyn E. Morris |
| author_sort | Kristin E. Follman |
| collection | DOAJ |
| description | Renal impairment (RI) is a highly prevalent disease which can alter the pharmacokinetics (PK) of xenobiotics, including those that are predominately metabolized. The expression and activity of drug metabolizing enzymes (DMEs) and protein binding of compounds has been demonstrated to be affected in RI. A simulation based approach allows for the characterization of the impact of changes in these factors on the PK of compounds which are highly metabolized and allows for improved prediction of PK in RI. Simulations with physiologically based pharmacokinetic (PBPK) modeling was utilized to define the impact of these factors in PK in RI for a model substrate, nifedipine. Changes in fraction unbound and DME expression/activity had profound effects on PK in RI. Increasing fraction unbound and DME expression resulted in a reduction in exposure of nifedipine, while the reduction of DME activity resulted in an increase in exposure. In vitro and preclinical data were utilized to inform simulations for nifedipine, sildenafil and zidovudine. Increasing fraction unbound and changes in the expression/activity of DMEs led to improved predictions of PK. Further characterization of the impact of RI on these factors is warranted in order to better inform a priori predictions of PK in RI. |
| first_indexed | 2024-04-11T22:46:38Z |
| format | Article |
| id | doaj.art-d82b0420cc614d10b267ea6f0a6ab0ae |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T22:46:38Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-d82b0420cc614d10b267ea6f0a6ab0ae2022-12-22T03:58:44ZengMDPI AGPharmaceutics1999-49232019-03-0111310510.3390/pharmaceutics11030105pharmaceutics11030105Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized CompoundsKristin E. Follman0Marilyn E. Morris1Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USADepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USARenal impairment (RI) is a highly prevalent disease which can alter the pharmacokinetics (PK) of xenobiotics, including those that are predominately metabolized. The expression and activity of drug metabolizing enzymes (DMEs) and protein binding of compounds has been demonstrated to be affected in RI. A simulation based approach allows for the characterization of the impact of changes in these factors on the PK of compounds which are highly metabolized and allows for improved prediction of PK in RI. Simulations with physiologically based pharmacokinetic (PBPK) modeling was utilized to define the impact of these factors in PK in RI for a model substrate, nifedipine. Changes in fraction unbound and DME expression/activity had profound effects on PK in RI. Increasing fraction unbound and DME expression resulted in a reduction in exposure of nifedipine, while the reduction of DME activity resulted in an increase in exposure. In vitro and preclinical data were utilized to inform simulations for nifedipine, sildenafil and zidovudine. Increasing fraction unbound and changes in the expression/activity of DMEs led to improved predictions of PK. Further characterization of the impact of RI on these factors is warranted in order to better inform a priori predictions of PK in RI.http://www.mdpi.com/1999-4923/11/3/105renal impairmentdrug metabolizing enzymeprotein bindingpharmacokineticssimulationphysiologically based pharmacokinetic modelingnifedipinesildenafilzidovudine |
| spellingShingle | Kristin E. Follman Marilyn E. Morris Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds Pharmaceutics renal impairment drug metabolizing enzyme protein binding pharmacokinetics simulation physiologically based pharmacokinetic modeling nifedipine sildenafil zidovudine |
| title | Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds |
| title_full | Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds |
| title_fullStr | Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds |
| title_full_unstemmed | Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds |
| title_short | Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds |
| title_sort | simulation based analysis of the impact of renal impairment on the pharmacokinetics of highly metabolized compounds |
| topic | renal impairment drug metabolizing enzyme protein binding pharmacokinetics simulation physiologically based pharmacokinetic modeling nifedipine sildenafil zidovudine |
| url | http://www.mdpi.com/1999-4923/11/3/105 |
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