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Uridine 5′‑diphospho‑glucuronosyltransferase 1A3 (UGT1A3) prediction of hepatic clearance of organic anion transporting polypeptide 1B3 (OATP1B3) substrate telmisartan by glucuronidation using in vitro–in vivo extrapolation (IVIVE) / Ewelina GABOR-WORWA, Anna KOWAL-CHWAST, Nilesh Gaud, Dawid Gogola, Peter Littlewood, Marek SMOLUCH, Krzysztof Brzózka, Kamil Kus // European Journal of Drug Metabolism and Pharmacokinetics ; ISSN 0378-7966. — 2024 — vol. 49 iss. 3, s. 393–403. — Bibliogr. s. 401–403, Abstr. — Publikacja dostępna online od: 2024-04-20. — E. Gabor-Worwa, A. Kowal-Chwast - dod. afiliacja: Ryvu Therapeutics S. A., Krakow

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Dane bibliometryczne

ID BaDAP153086
Data dodania do BaDAP2024-05-10
Tekst źródłowyURL
Rok publikacji2024
Typ publikacjiartykuł w czasopiśmie
Otwarty dostęptak
Czasopismo/seriaEuropean Journal of Drug Metabolism and Pharmacokinetics


Background and Objective: The prediction of pharmacokinetic parameters for drugs metabolised by cytochrome P450 enzymes has been the subject of active research for many years, while the application of in vitro–in vivo extrapolation (IVIVE) techniques for non-cytochrome P450 enzymes has not been thoroughly evaluated. There is still no established quantitative method for predicting hepatic clearance of drugs metabolised by uridine 5′-diphospho-glucuronosyltransferases (UGTs), not to mention those which undergo hepatic uptake. The objective of the study was to predict the human hepatic clearance for telmisartan based on in vitro metabolic stability and hepatic uptake results. Methods: Telmisartan was examined in liver systems, allowing to estimate intrinsic clearance (CLint, in vitro) based on the substrate disappearance rate with the use of liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Obtained CLint, in vitro values were corrected for corresponding unbound fractions. Prediction of human hepatic clearance was made from scaled unbound CLint, in vitro data with the use of the well-stirred model, and finally referenced to the literature value of observed clearance in humans, allowing determination of the essential scaling factors. Results: The in vitro scaled CLint, in vitro by UGT1A3 was assessed using three systems, human hepatocytes, liver microsomes, and recombinant enzymes. Obtained values were scaled and hepatic metabolism clearance was predicted, resulting in significant clearance underprediction. Utilization of the extended clearance concept (ECC) and hepatic uptake improved prediction of hepatic metabolism clearance. The scaling factors for hepatocytes, assessing the in vitro–in vivo difference, changed from sixfold difference to only twofold difference with the application of the ECC. Conclusions: The study showed that taking into consideration hepatic uptake of a drug allows us to obtain satisfactory scaling factors, hence enabling the prediction of in vivo hepatic glucuronidation from in vitro data.

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fragment książki
Prediction of hepatic clearance of oxazepam by glucuronidation using in vitro-in vivo extrapolation / Ewelina GABOR-WORWA, Anna KOWAL-CHWAST, Nilesh Gaud, Dawid Gogola, Kamil Kuś, Peter Littlewood, Krzysztof Brzózka, Marek SMOLUCH // W: XVI Kopernikańskie seminarium doktoranckie : Toruń, 29-30. 06. 2023 r. / red. Karolina Jeżak. — Toruń : Uniwersytet Mikołaja Kopernika, [2023]. — S. 106. — Bibliogr. s. 106. — E. Gabor-Worwa, A. Kowal-Chwast – dod. afiliacja: Ryvu Therapeutics SA
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