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PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5′-Diphospho-glucuronosyltransferase Substrates

1
Early Clinical Development, Department of Clinical Pharmacology Oncology, Pfizer, Boulder, CO 80301, USA
2
Simulations Plus Inc., Lancaster, CA 93534, USA
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PKPD Department, Pierre Fabre Laboratories, 31100 Toulouse, France
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Material & Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
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Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, Springhouse, PA 19477, USA
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Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, 4070 Basel, Switzerland
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Admescope Ltd., Fi-90620 Oulu, Finland
*
Author to whom correspondence should be addressed.
Academic Editor: Jonathan Paul Mochel
Pharmaceutics 2021, 13(9), 1325; https://doi.org/10.3390/pharmaceutics13091325
Received: 14 July 2021 / Revised: 17 August 2021 / Accepted: 18 August 2021 / Published: 24 August 2021
Uridine 5′-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug–drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro–in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates. View Full-Text
Keywords: GastroPlus; PBPK; UGT; intestinal metabolism; gut extraction; absorption modeling; oral bioavailability; IVIVE; phase II metabolism GastroPlus; PBPK; UGT; intestinal metabolism; gut extraction; absorption modeling; oral bioavailability; IVIVE; phase II metabolism
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MDPI and ACS Style

Reddy, M.B.; Bolger, M.B.; Fraczkiewicz, G.; Del Frari, L.; Luo, L.; Lukacova, V.; Mitra, A.; Macwan, J.S.; Mullin, J.M.; Parrott, N.; Heikkinen, A.T. PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5′-Diphospho-glucuronosyltransferase Substrates. Pharmaceutics 2021, 13, 1325. https://doi.org/10.3390/pharmaceutics13091325

AMA Style

Reddy MB, Bolger MB, Fraczkiewicz G, Del Frari L, Luo L, Lukacova V, Mitra A, Macwan JS, Mullin JM, Parrott N, Heikkinen AT. PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5′-Diphospho-glucuronosyltransferase Substrates. Pharmaceutics. 2021; 13(9):1325. https://doi.org/10.3390/pharmaceutics13091325

Chicago/Turabian Style

Reddy, Micaela B., Michael B. Bolger, Grace Fraczkiewicz, Laurence Del Frari, Laibin Luo, Viera Lukacova, Amitava Mitra, Joyce S. Macwan, Jim M. Mullin, Neil Parrott, and Aki T. Heikkinen 2021. "PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5′-Diphospho-glucuronosyltransferase Substrates" Pharmaceutics 13, no. 9: 1325. https://doi.org/10.3390/pharmaceutics13091325

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