Human hepatocytes and cytochrome P450-selective inhibitors predict variability in human drug exposure more accurately than human recombinant P450s.
Autor: | Lindmark B; Cardiovascular, Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden., Lundahl A; Cardiovascular, Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden., Kanebratt KP; Cardiovascular, Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden., Andersson TB; Cardiovascular, Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden., Isin EM; Cardiovascular, Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden. |
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Jazyk: | angličtina |
Zdroj: | British journal of pharmacology [Br J Pharmacol] 2018 Jun; Vol. 175 (11), pp. 2116-2129. Date of Electronic Publication: 2018 Apr 19. |
DOI: | 10.1111/bph.14203 |
Abstrakt: | Background and Purpose: Drugs metabolically eliminated by several enzymes are less vulnerable to variable compound exposure in patients due to drug-drug interactions (DDI) or if a polymorphic enzyme is involved in their elimination. Therefore, it is vital in drug discovery to accurately and efficiently estimate and optimize the metabolic elimination profile. Experimental Approach: CYP3A and/or CYP2D6 substrates with well described variability in vivo in humans due to CYP3A DDI and CYP2D6 polymorphism were selected for assessment of fraction metabolized by each enzyme (fm Key Results: Predicted changes in exposure were within twofold of reported in vivo values using fm Conclusions and Implications: The results suggest that variability in human drug exposure due to DDI and enzyme polymorphism can be accurately predicted using fm (© 2018 The British Pharmacological Society.) |
Databáze: | MEDLINE |
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