Journal ArticleDOI
The Utility of in Vitro Cytochrome P450 Inhibition Data in the Prediction of Drug-Drug Interactions
R. Scott Obach,Robert L. Walsky,Karthik Venkatakrishnan,Emily A. Gaman,J. Brian Houston,Larry M. Tremaine +5 more
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TLDR
Findings support the conclusion that P450 in vitro inhibition data are valuable in designing clinical DDI study strategies and can be used to predict the magnitudes of DDI.Abstract:
The accuracy of in vitro inhibition parameters in scaling to in vivo drug-drug interactions (DDI) was examined for over 40 drugs using seven human P450-selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C max , estimated hepatic inlet C max , fraction unbound, and fraction of the probe drug cleared by the inhibited enzyme) to predict increases in exposure to probe drugs, and the predictions were compared with in vivo DDI gathered from clinical studies reported in the scientific literature. For drugs that had been tested as precipitants of drug interactions for more than one P450 in vivo, the order of inhibitory potencies in vitro generally aligned with the magnitude of the in vivo interactions. With the exception of many drugs known to be mechanism-based inactivators, the use of in vitro IC 50 , the fraction of the affected drug metabolized by the target enzyme [ f m(CYP) ] and an estimate of free hepatic inlet C max , was generally successful in identifying those drugs that cause at least a 2-fold increase in the exposure to P450 marker substrate drugs. For CYP3A, incorporation of inhibition of both hepatic and intestinal metabolism was needed for the prediction of DDI. Many CYP3A inhibitors showed a different inhibitory potency for three different CYP3A marker activities; however, these differences generally did not alter the conclusions regarding whether a drug would cause a CYP3A DDI in vivo. Overall, these findings support the conclusion that P450 in vitro inhibition data are valuable in designing clinical DDI study strategies and can be used to predict the magnitudes of DDI.read more
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Membrane transporters in drug development.
Kathleen M. Giacomini,Shiew-Mei Huang,Donald J. Tweedie,Leslie Z. Benet,Kim L. R. Brouwer,Xiaoyan Chu,Amber Dahlin,Raymond Evers,Volker Fischer,Kathleen M. Hillgren,Keith Hoffmaster,Toshihisa Ishikawa,Dietrich Keppler,Richard B. Kim,Caroline A. Lee,Mikko Niemi,Joseph W. Polli,Yuicchi Sugiyama,Peter W. Swaan,Joseph A. Ware,Stephen H. Wright,Sook Wah Yee,Maciej J. Zamek-Gliszczynski,Lei Zhang +23 more
TL;DR: Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions, as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
Journal ArticleDOI
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
Patricio Godoy,Nicola J. Hewitt,Ute Albrecht,Melvin E. Andersen,Nariman Ansari,Sudin Bhattacharya,Johannes G. Bode,Jennifer Bolleyn,Christoph Borner,J Böttger,Albert Braeuning,Robert A. Budinsky,Britta Burkhardt,Neil R. Cameron,Giovanni Camussi,Chong Su Cho,Yun Jaie Choi,J. Craig Rowlands,Uta Dahmen,Georg Damm,Olaf Dirsch,María Teresa Donato,Jian Dong,Steven Dooley,Dirk Drasdo,Dirk Drasdo,Dirk Drasdo,Rowena Eakins,Karine Sá Ferreira,Valentina Fonsato,Joanna Fraczek,Rolf Gebhardt,Andrew Gibson,Matthias Glanemann,Christopher E. Goldring,María José Gómez-Lechón,Geny M. M. Groothuis,Lena Gustavsson,Christelle Guyot,David Hallifax,Seddik Hammad,Adam S. Hayward,Dieter Häussinger,Claus Hellerbrand,Philip Hewitt,Stefan Hoehme,Hermann-Georg Holzhütter,J. Brian Houston,Jens Hrach,Kiyomi Ito,Hartmut Jaeschke,Verena Keitel,Jens M. Kelm,B. Kevin Park,Claus Kordes,Gerd A. Kullak-Ublick,Edward L. LeCluyse,Peng Lu,Jennifer Luebke-Wheeler,Anna Lutz,Daniel J. Maltman,Madlen Matz-Soja,Patrick D. McMullen,Irmgard Merfort,Simon Messner,Christoph Meyer,Jessica Mwinyi,Dean J. Naisbitt,Andreas K. Nussler,Peter Olinga,Francesco Pampaloni,Jingbo Pi,Linda J. Pluta,Stefan Przyborski,Anup Ramachandran,Vera Rogiers,Cliff Rowe,Celine Schelcher,Kathrin Schmich,Michael Schwarz,Bijay Singh,Ernst H. K. Stelzer,Bruno Stieger,Regina Stöber,Yuichi Sugiyama,Ciro Tetta,Wolfgang E. Thasler,Tamara Vanhaecke,Mathieu Vinken,Thomas S. Weiss,Agata Widera,Courtney G. Woods,Jinghai James Xu,Kathy Yarborough,Jan G. Hengstler +94 more
TL;DR: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro and how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes.
Book
Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization
Edward H. Kerns,Li Di +1 more
TL;DR: Practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance are provided.
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Physiologically-based pharmacokinetics in drug development and regulatory science.
TL;DR: Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation.
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Inhibition and induction of human cytochrome P450 enzymes: current status.
Olavi Pelkonen,Miia Turpeinen,Miia Turpeinen,Miia Turpeinen,Jukka Hakkola,Paavo Honkakoski,Janne Hukkanen,Hannu Raunio +7 more
TL;DR: This review covers both inhibition and induction of CYP enzymes, always keeping in mind the basic mechanisms on which to build predictive and preventive in vitro approaches.
References
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Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System
Chi-Yuan Wu,Leslie Z. Benet +1 more
TL;DR: It is suggested that a Biopharmaceutics Drug Disposition Classification System (BDDCS) using elimination criteria may expand the number of Class 1 drugs eligible for a waiver of in vivo bioequivalence studies and provide predictability of drug disposition profiles for Classes 2, 3, and 4 compounds.
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The conduct of in vitro and in vivo drug-drug interaction studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) perspective
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Journal ArticleDOI
Validated assays for human cytochrome P450 activities.
Robert L. Walsky,R. Scott Obach +1 more
TL;DR: 12 semiautomated assays for human P450 marker substrate activities have been developed and validated using approaches described in the GLP (good laboratory practices) and demonstrated high precision and were within the range of values previously reported in the scientific literature.
Journal ArticleDOI
The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin.
J. Christopher Gorski,David R. Jones,Barbara D. Haehner‐Daniels,Mitchell A. Hamman,Edward M. O'Mara,Stephen D. Hall +5 more
TL;DR: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP2A substrates midazolam and clarithromycin, a large number of mice were fitted with EMTs and the objective was to establish a ‘spatially aggregating force’ between the two substrates.
Journal ArticleDOI
Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance
Maria Gabriella Scordo,Maria Gabriella Scordo,Maria Gabriella Scordo,Vittorio Pengo,Vittorio Pengo,Vittorio Pengo,Edoardo Spina,Edoardo Spina,Edoardo Spina,Marja Liisa Dahl,Marja Liisa Dahl,Marja Liisa Dahl,Milena Gusella,Milena Gusella,Milena Gusella,Roberto Padrini,Roberto Padrini,Roberto Padrini +17 more
TL;DR: The objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance.
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