The use of in vitro metabolic stability for rapid selection of compounds in early discovery based on their expected hepatic extraction ratios

• Published in: Pharmaceutical research Vol. 19; no. 11; pp. 1606 - 1621
• Main Authors: YAU YI LAU, KRISHNA, Gopal, YUMIBE, Nathan P, GROTZ, Diane E, SAPIDOU, Elpida, NORTON, Laura, INHOU CHU, CHEN, Cliff, SOARES, A. D, LIN, Chin-Chung
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.11.2002; Springer Nature B.V
• Subjects: Animals; Bioavailability; Biological and medical sciences; Caco-2 Cells; Dehydrogenases; Drug dosages; Enzyme Stability - drug effects; Enzyme Stability - physiology; Forecasting; General pharmacology; Glucose; Humans; Liver; Macaca fascicularis; Medical sciences; Metabolic Clearance Rate - drug effects; Metabolic Clearance Rate - physiology; Metabolism; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Neural networks; Pharmaceutical Preparations - metabolism; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Ratios; Technology, Pharmaceutical - methods; Stability; Digestive system; Estimation; Liver; Biological transport; Prediction; Monkey; Microsome; Metabolism; In vitro; hepatic extraction ratio; In vivo; Vertebrata; Mammalia; in vitro-in vivo correlation; Caco-2; rapid screening; Animal; Established cell line; Primates; Extraction; Pharmacokinetics; Tumor cell; liver microsomes
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1020765025857

The in vivo hepatic extraction ratio of cynomolgus monkeys was correlated with the corresponding in vitro extraction ratios that were determined in monkey microsomal incubations. For compounds that are eliminated mainly through liver phase I metabolism, the extraction ratio calculated from liver microsomal stability studies should correlate with their in vivo hepatic extraction ratios and also with their oral bioavailability in monkey. We used both well-stirred and parallel tube models of intrinsic clearance for the correlation. We also calculated extraction ratios for compounds within a given therapeutic area from fraction absorbed values that were estimated from the Caco-2 absorption model. The present data show that in vitro extraction ratios in monkey microsomes are predictive of the in vivo hepatic extraction ratios in monkeys. All compounds with high extraction ratio (>70%) in vivo were successfully classified as high-extraction-ratio compounds based on the in vitro monkey microsomal stability data. From the results of this study, it appears that the parallel tube model provided a slightly better classification than the well-stirred model. CONCULUSIONS: The present method appears to be a valuable tool to rapidly screen and prioritize compounds with respect to liver first-pass metabolism in monkeys at an early phase of drug discovery.