Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance Predictions
Accurate predictions of drug uptake transporter involvement in renal excretion of xenobiotics require determination of in vitro transport kinetic parameters under initial-rate conditions. The purpose of the present study was to determine how changing the incubation time from initial rate to steady s...
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MDPI AG
2023-05-01
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| Series: | Journal of Xenobiotics |
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| Online Access: | https://www.mdpi.com/2039-4713/13/2/16 |
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| author | Aaron O. Buaben Ryan M. Pelis |
| author_facet | Aaron O. Buaben Ryan M. Pelis |
| author_sort | Aaron O. Buaben |
| collection | DOAJ |
| description | Accurate predictions of drug uptake transporter involvement in renal excretion of xenobiotics require determination of in vitro transport kinetic parameters under initial-rate conditions. The purpose of the present study was to determine how changing the incubation time from initial rate to steady state influences ligand interactions with the renal organic anion transporter 1 (OAT1), and the impact of the different experimental conditions on pharmacokinetic predictions. Transport studies were performed with Chinese hamster ovary cells expressing OAT1 (CHO-OAT1) and the Simcyp Simulator was used for physiological-based pharmacokinetic predictions. Maximal transport rate and intrinsic uptake clearance (CL<sub>int</sub>) for PAH decreased with increasing incubation time. The CL<sub>int</sub> values ranged 11-fold with incubation times spanning from 15 s (CL<sub>int,15s</sub>, initial rate) to 45 min (CL<sub>int,45min</sub>, steady state). The Michaelis constant (K<sub>m</sub>) was also influenced by the incubation time with an apparent increase in the Km value at longer incubation times. Inhibition potency of five drugs against PAH transport was tested using incubation times of either 15 s or 10 min. There was no effect of time on inhibition potency for omeprazole or furosemide, whereas indomethacin was less potent, and probenecid (~2-fold) and telmisartan (~7-fold) more potent with the longer incubation time. Notably, the inhibitory effect of telmisartan was reversible, albeit slowly. A pharmacokinetic model was developed for PAH using the CL<sub>int,15s</sub> value. The simulated plasma concentration-time profile, renal clearance, and cumulative urinary excretion-time profile of PAH agreed well with reported clinical data, and the PK parameters were sensitive to the time-associated CL<sub>int</sub> value used in the model. |
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| language | English |
| last_indexed | 2024-03-11T02:16:07Z |
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| series | Journal of Xenobiotics |
| spelling | doaj.art-1c4dd1fcaec047bb8652360939252eeb2023-11-18T11:09:53ZengMDPI AGJournal of Xenobiotics2039-47052039-47132023-05-0113220521710.3390/jox13020016Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance PredictionsAaron O. Buaben0Ryan M. Pelis1Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, CanadaDrug Disposition, Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USAAccurate predictions of drug uptake transporter involvement in renal excretion of xenobiotics require determination of in vitro transport kinetic parameters under initial-rate conditions. The purpose of the present study was to determine how changing the incubation time from initial rate to steady state influences ligand interactions with the renal organic anion transporter 1 (OAT1), and the impact of the different experimental conditions on pharmacokinetic predictions. Transport studies were performed with Chinese hamster ovary cells expressing OAT1 (CHO-OAT1) and the Simcyp Simulator was used for physiological-based pharmacokinetic predictions. Maximal transport rate and intrinsic uptake clearance (CL<sub>int</sub>) for PAH decreased with increasing incubation time. The CL<sub>int</sub> values ranged 11-fold with incubation times spanning from 15 s (CL<sub>int,15s</sub>, initial rate) to 45 min (CL<sub>int,45min</sub>, steady state). The Michaelis constant (K<sub>m</sub>) was also influenced by the incubation time with an apparent increase in the Km value at longer incubation times. Inhibition potency of five drugs against PAH transport was tested using incubation times of either 15 s or 10 min. There was no effect of time on inhibition potency for omeprazole or furosemide, whereas indomethacin was less potent, and probenecid (~2-fold) and telmisartan (~7-fold) more potent with the longer incubation time. Notably, the inhibitory effect of telmisartan was reversible, albeit slowly. A pharmacokinetic model was developed for PAH using the CL<sub>int,15s</sub> value. The simulated plasma concentration-time profile, renal clearance, and cumulative urinary excretion-time profile of PAH agreed well with reported clinical data, and the PK parameters were sensitive to the time-associated CL<sub>int</sub> value used in the model.https://www.mdpi.com/2039-4713/13/2/16kidneydrug transportorganic anion transporter 1physiological-based pharmacokineticsMechanistic Kidney modelrenal clearance |
| spellingShingle | Aaron O. Buaben Ryan M. Pelis Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance Predictions Journal of Xenobiotics kidney drug transport organic anion transporter 1 physiological-based pharmacokinetics Mechanistic Kidney model renal clearance |
| title | Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance Predictions |
| title_full | Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance Predictions |
| title_fullStr | Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance Predictions |
| title_full_unstemmed | Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance Predictions |
| title_short | Incubation Time Influences Organic Anion Transporter 1 Kinetics and Renal Clearance Predictions |
| title_sort | incubation time influences organic anion transporter 1 kinetics and renal clearance predictions |
| topic | kidney drug transport organic anion transporter 1 physiological-based pharmacokinetics Mechanistic Kidney model renal clearance |
| url | https://www.mdpi.com/2039-4713/13/2/16 |
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