The right compound in the right assay at the right time: An integrated discovery DMPK strategy

Drug Metabolism Reviews

Volumn 44, Issue 3, 2012, Pages 224-252

  Ballard, Peter ^a   Brassil, Patrick ^a   Bui, Khanh H ^a   Dolgos, Hugues ^b,c   Petersson, Carl ^b   Tunek, Anders ^b   Webborn, Peter J H ^a  

^a ASTRAZENECA   (United Kingdom)

^b ASTRAZENECA R AND D   (Sweden)

^c MERCK SERONO S A   (Switzerland)

Author keywords

absorption; clearance; CNS distribution; Compound optimization; design make test analyze cycles; drug drug interactions; human pharmacokinetic and dose predictions; metabolites; transporters

Indexed keywords

ADENOSINE DEAMINASE; ALDEHYDE DEHYDROGENASE; ALDEHYDE OXIDASE; CYTOCHROME P450 3A4; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 2; NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; PREGNANE X RECEPTOR;

AREA UNDER THE CURVE; ARTIFICIAL MEMBRANE; BIOTRANSFORMATION; CEREBROSPINAL FLUID; COMPETITIVE INHIBITION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DEGRADATION; DRUG DETERMINATION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG EXCRETION; DRUG HALF LIFE; DRUG INDUSTRY; DRUG METABOLISM; DRUG RESEARCH; DRUG SCREENING; DRUG STABILITY; DRUG TRANSFORMATION; DRUG TRANSPORT; DRUG UPTAKE; ENZYME SUBSTRATE; GLOMERULUS FILTRATION RATE; HEPATOBILIARY SYSTEM; HIGH THROUGHPUT SCREENING; HUMAN; IN VITRO STUDY; KIDNEY BLOOD FLOW; KIDNEY CLEARANCE; LIPOPHILICITY; LIVER CELL; MAXIMUM PLASMA CONCENTRATION; MEMBRANE PERMEABILITY; NONHUMAN; PARTITION COEFFICIENT; PHARMACODYNAMICS; PHARMACOPHORE; PHENOTYPE; PHYSICAL CHEMISTRY; PREDICTIVE VALUE; QUANTITATIVE ANALYSIS; REVIEW; STEADY STATE; STRUCTURE ACTIVITY RELATION; TANDEM MASS SPECTROMETRY;

ANIMALS; DECISION MAKING, ORGANIZATIONAL; DRUG EVALUATION, PRECLINICAL; DRUG INDUSTRY; DRUG INTERACTIONS; DRUGS, INVESTIGATIONAL; HUMANS; METABOLIC CLEARANCE RATE; METABOLIC DETOXICATION, DRUG;

EID: 84863809113     PISSN: 03602532     EISSN: 10979883     Source Type: Journal    
DOI: 10.3109/03602532.2012.691099     Document Type: Review

References (148)

1. Amidon, G. L., Lennernas, H., Shah, V. P., Crison, J. R. (1995). A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413-420.
2. Anderson, S., Luffer-Atlas, D., Knadle, M. P. (2009). Predicting circulating human metabolites: how good are we? Chem Res Toxicol 22:243-256.
3. Afzelius, L., Hasselgren Arnby, C., Broo, A., Carlsson, L., Isaksson, C., Jurva, U., et al. (2007). State-of-the-art tools for computational site of metabolism predictions: comparative analysis, mechanistic insights, and future applications. Drug Metab Rev 39:61-86.
4. Arrowsmith, J. (2011a). Trial watch: phase III and submission failures: 2007-2010. Nat Rev Drug Disc 10:87.
5. Arrowsmith, J. (2011b). Trial watch: phase II failures: 2008-2010. Nat Rev Drug Disc 10:328-329.
6. Artursson, P., Karlsson, J. (1991). Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 175:880-885.
7. Artursson, P., Palm, K., Luthman, K. (2001). Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev 46:27-43.
8. Avdeef, A. (2005). The rise of PAMPA. Expert Opin Drug Metab Toxicol 1:325-342.
9. Baillie, T. A. (2006). Future of toxicology metabolic activation and drug design: challenges and opportunities in chemical toxicology. Chem Res Toxicol 19:889-893.
10. Bell, L., Bickford, S., Nguyen, P. H., Wang, J., He, T., Zhang, B., et al. (2008). Evaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery. J Biomol Screen 13:343-353. (Pubitemid 351793985)
11. Berellini, G., Springer, C., Waters, N. J., Lombardo, R. (2009). In silico prediction of volume of distribution in human using linear and nonlinear models on a 669 compound data set. J Med Chem 52:4488-4495.
12. Beresford, A. P., Segall, M., Tarbit, M.H. (2004). In silico prediction of ADME properties: are we making progress. Curr Op Drug Dis Dev 7:36-42. (Pubitemid 44111911)
13. Bjornsson, T., Callaghan, J., Einolf, J. H., Fischer, V., Gan, L., Grimm, S., et al. (2003). The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol 43:443-469. (Pubitemid 36506147)
14. Bortolato, M., Chen, K., Shih, J. C. (2008). Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev 60:1527-1533.
15. Bredberg, U., Paalzow, L. (1990). Pharmacokinetics of methylergometrine in the rat: evidence for enterohepatic recirculation by a linked-rat model. Pharm Res 7:14-20. (Pubitemid 20115792)
16. Brown, C. D., Sayer, R., Windass, A. S., Haslam, I. S., De Broe, M. E., D'Haese, P. C., et al. (2008). Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling. Toxicol Appl Pharmacol 233:428-438.
17. Cashman, J. R. (2008). Role of flavin-containing monooxygenase in drug development. Expert Opin Drug Metab Toxicol 4:1507-1521.
18. Chiba, M., Ishii, Y., Sugiyama, Y. (2009). Prediction of hepatic clearance in human from in vitro data for successful drug development. Am Assoc Pharm Sci J 11:262-276.
19. Cohen, A. (2008). Pharmacokinetic and pharmacodynamic data to be derived from early-phase drug development: designing informative human pharmacology studies. Clin Pharmacokinet 47:373-381.
20. Cossum, P. A. (1988). Role of the red blood cell in drug metabolism. Biopharm Drug Dispos 9:321-336.
21. Cruciani, G., Carosati, E., De Boeck, B., Ethirajulu, K., Mackie, C., Howe, T., et al. (2005). MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. J Med Chem 48:6970-6979. (Pubitemid 41533118)
22. Cvetkovic, M., Leake, B., Fromm, M. F., Wilkinson G. R., Kim R. B. (1999). OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Met Disp 27:866-871. (Pubitemid 29347585)
23. Damle, B. D., Uderman, H., Biswas, P., Crownover, P., Lin, C., Glue, P. (2009). Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite. Br J Clin Pharmacol 68:682-689.
24. Danhof, M., Alvan, G., Dahl, S. G., Kuhlmann, J., Paintaud, G. (2005). Mechanism-based pharmacokinetic-pharmacodynamic modeling-a new classification of biomarkers. Pharm Res 22:1432-1437. (Pubitemid 41215882)
25. Darwich, S., Neuhoff, S., Jamei, M., Rostami-Hodjegan, A. (2010). Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: A simulation assessment using the "Advanced dissolution, absorption, metabolism (ADAM)" model. Curr Drug Met 11:716-729.
26. Davies, M. I. (1999). A review of microdialysis sampling for pharmacokinetic applications. Anal Chim Acta 379:227-249.
27. Dawson, S., Stahl, S., Paul, N., Barber, J., Kenna, J. G. (2012). In vitro inhibition of the bile salt export pump correlates with risk of cholestatic druginduced liver injury in humans. Drug Met Disp 40:130-138.
28. Di, L., Kerns, E. H. (2003). Profiling drug-like properties in discovery research. Curr Opin Chem Biol 7:402-408. (Pubitemid 36782368)
29. Di, L., Kerns, H., Carte, G. (2008). Strategies to assess blood-brain barrier penetration. Expert Opin Drug Discov 3:677-687. (Pubitemid 351890679)
30. Didziapetris, R., Japertas, P., Avdeef, A., Petrauskas, A. (2003). Classification analysis of P-glycoprotein substrate specificity. J Drug Target 11:391-406. (Pubitemid 38455825)
31. Doan, K. M. M., Humphreys, J. E., Webster, L. O., Wring, S. A., Shampine, L. J., Serabjit-Singh, J. et al. (2002). Passive permeability and p-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharm Exp Ther 303:1029-1037. (Pubitemid 35424386)
32. Doddareddy, M. R., Cho, Y. S., Koh, H. Y., Kim, D. H., Pae, A. N. (2006). In silico renal clearance model using classical volsurf approach. J Chem Inf Model 46:1312-1320. (Pubitemid 43999174)
33. Doran, A., Obach, R. S., Smith, B. J., Hosea, N. A., Becker, S., Callegari, E., et al. (2005). The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165-174. (Pubitemid 40023528)
34. Eisenblatter, T., Galla, H. J. (2002). A new multidrug resistance protein at the blood-brain barrier. Biochem Biophys Res Comm 293:1273-1278. (Pubitemid 34681079)
35. European Medicines Agency. (2010). Guideline on the investigation of drug interactions. Available at: http://www.ema.europa.eu/ docs/en-GB/document- library/Scientific-guideline/2010/05/WC500090112.pdf. Accessed on February 11, 2011.
36. Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., Baillie, T. A. (2004). Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17:3-16. (Pubitemid 38134055)
37. Eyal, S., Hsiao, P., Unadkat, J. D. (2009). Drug interactions at the bloodbrain barrier: fact or fantasy? Pharmacol Ther 123:80-104.
38. Fagerholm, U. (2008). Prediction of human pharmacokinetics-biliary and intestinal clearance and enterohepatic circulation. J Pharm Pharmacol 60:535-542.
39. Fahmi, O. A., Boldt, S., Kish, M., Obach, R. S., Tremaine, L. M. (2008). Prediction of drug-drug interactions from in vitro induction data: application of the relative induction score approach using cryopreserved human hepatocytes. Drug Metab Dis 36:1971-1974.
40. Feng, B., LaPerle, J. L., Chang, G., Varma, M. V. S. (2010). Renal clearance in drug discovery and development: molecular descriptors, drug transporters, and disease state. Exp Opin Drug Metab Toxicol 6:939-952.
41. Fenner, K. S., Jones, H. M., Ullah, M., Kempshall, S., Dickins, M., Lai, Y., et al. (2012). The evolution of the OATP hepatic uptake transport protein family in DMPK sciences: from obscure liver transporters to key determinants of hepatobiliary clearance. Xenobiotica 42:28-45.
42. Fowler, S., Zhang, H. (2008). In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug-drug interactions. Am Assoc Pharm Sci J 10:410-424.
43. Fridén, M., Ducrozet, F., Middleton, B., Antonsson, M., Bredberg, U., Hammarlund-Udenaes, M. (2009a). Development of a high-throughput brain slice method for studying drug distribution in the central nervous system. Drug Metab Dispos 37:1226-1233.
44. Fridén, M., Winiwarter, S., Jerndal, G., Bengtsson, O., Wan, H., Bredberg, U., et al. (2009b). Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. J Med Chem 52:6233-6243.
45. Fridén, M., Ljungqvist, H., Middleton, B., Bredberg, U., Hammarlund- Udenaes, M. (2010). Improved measurement of drug exposure in brain using drug-specific correction for residual blood. J Cereb Blood Flow Metab 30:150-161.
46. Fridén, M., Bergstrom, F., Wan, H., Rehngren, M., Ahlin, G., Hammarlund-Udenaes, M., et al. (2011). Measurement of unbound drug exposure in the brain: modelling of pH partitioning explains diverging results between the brain slice and brain homogenate methods. Drug Metab Dis 39:353-362.
47. Gabrielsson, J., Green, A. R. (2009). Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology. J Pharmacol Exp Ther 331:767-774.
48. Gabrielsson, J., Dolgos, H., Gillberg, P. G., Bredberg, U., Benthem, B., Duker, G. (2009). Early integration of pharmacokinetic and dynamic reasoning is essential for optimal development of lead compounds: strategic considerations. Drug Discov Today 14:358-372.
49. Gabrielsson, J., Green, A. R., Van der Graaf, P. H. (2010). Optimising in vivo pharmacology studies--Practical PKPD considerations. J Pharmacol Toxicol Methods 61:146-156.
50. Galetin, A., Gertz, M., Houston, J. B. (2008). Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions. Expert Opin Drug Metab Toxicol 4:909-922.
51. Garcia, M. J., Reinoso, R. F., Sanchez Navarro, A., Prous, J. R. (2003). Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol 25:457-481. (Pubitemid 37203702)
52. Gertz, M., Harrison, A., Houston, J. B., Galetin, A. (2010). Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Dispos 38:1147-1158.
53. Ghibellini, G., Vasist, L. S., Leslie, E. M., Heizer, W. D., Kowalsky, R. J., Calvo, B. F., et al. (2007). In vitro-in vivo correlation of hepatobiliary drug clearance in humans. Clin Pharmacol Ther 81:406-413. (Pubitemid 46364478)
54. Giacomini, K. M., Huang, S-M., Tweedie, D. J., Benet, L. Z., Brouwer, K. L. M., Chu, X., et al. (2010). Membrane transporters in drug development. Nat Rev Drug Discov 9:215-236.
55. Gleeson, P., Davis, A., Chohan, K., Paine, S., Boyer, S., Gavaghan, C. L., et al. (2007). Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models. J Comput Aided Mol Des 21:559-573. (Pubitemid 50005007)
56. Griffin, L., Annaert, P., Brouwer, K. L. R. (2011). Influence of drug transport proteins on the pharmacokinetics and drug interactions of HIV protease inhibitors. J Pharm Sci 100:3636-3654.
57. Grime, K. H., Bird, J., Ferguson, D., Riley, R. J. (2009). Mechanism-based inhibition of cytochrome P450 enzymes: an evaluation of early decision making in vitro approaches and drug-drug interaction prediction methods. Eur J Pharm Sci 36:175-191.
58. Gu, X., Manautou, J. E. (2010). Regulation of hepatic ABCC transporters by xenobiotics and in disease states. Drug Metab Rev 42:482-538.
59. Guengerich, F. P. (2005). Principles of covalent binding of reactive metabolites and examples of activation of bis-electrophiles by conjugation. Arch Biochem Biophys 433:369-378.
60. Harmsen, S., Meijerman, I., Beijnen, J. H., Schellens, J. H. M. (2009). Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer Chem Pharm 64:35-43.
61. Hitchcock, S., Pennington, L. (2006). Structure-brain exposure relationships. J Med Chem 49:7559-7583. (Pubitemid 46033646)
62. Hirano, M., Maeda, K., Shitara, Y., Sugiyama, Y. (2006). Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Disp 34:1229-1236.
63. Huang, S., Strong, J., Zhang, L., Reynolds, K., Nallani, S., Temple, R., et al. (2008). New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol 48:662-670. (Pubitemid 351713150)
64. Ito, K., Brown, H. S., Houston, J. B. (2004). Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br J Clin Pharm 57:473-486. (Pubitemid 38519653)
65. Jana, S., Mandlekar, S. (2009). Role of phase II drug metabolizing enzymes in cancer chemoprevention. Curr Drug Metab 10:595-616.
66. Johnson, T. W., Dress, K. R., Edwards, M. (2009). Using the golden triangle to optimise clearance and oral absorption. Bioorg Med Chem Lett 19:5560-5564.
67. Johnson, K. C., Swindell, A. C. (1996). Guidance in the setting of drug particle size specifications to minimise variability in absorption. Pharm Res 13:1795-1798. (Pubitemid 27034109)
68. Ju, C., Uetrecht, J. P. (2002). Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding, and the regulation of the immune system. Curr Drug Metab 3:367-377. (Pubitemid 34778003)
69. Kandel, E. R., Schwartz, J. H., Jessel, T. M. (2000). Principles of neural science, 4th ed. New York: McGraw-Hill.
70. Kanebratt, K. P., Andersson, T. B. (2008). HepaRG cells as an in vitro model for evaluation of cytochrome. Drug Metab Disp 36:137-145.
71. Kerns, E. H., Li, D. (2003). Pharmaceutical profiling in drug discovery. Drug Disc Today 8:316-323. (Pubitemid 36332223)
72. Kiang, T. K. L., Ensom, M. H. H., Chang, T. K. H. (2005). UDPglucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther 106:97-132.
73. Kola, I., Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates. Nat Rev Drug Dis 3:711-716.
74. Ku, W. K., Bigger, A., Brambilla, G., Glatt, H., Gocke, E., Guzzie, P. J., et al. (2007). Strategy for genotoxicity testing-metabolic considerations. Mutat Res 627:59-77. (Pubitemid 46091767)
75. Kusuhara, H., Sugiyama, Y. (2010). Pharmacokinetic modeling of the hepatobiliary transport mediated by cooperation of uptake and efflux transporters. Drug Metab Rev 42:539-550.
76. de Lange, E. C., Danhof, M., de Boer, A. G., Breimer, D. D. (1997). Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood-brain barrier. Brain Res Rev 25:27-49.
77. Lappin, G., Garner, R. C. (2008). The utility of microdosing over the past 5 years. Exp Op Drug Met Tox 4:1499-1506.
78. Lavé, T., Chapman, K., Goldsmith, P., Rowland, M. (2009). Human clearance prediction: shifting the paradigm. Expert Opin Drug Metab Toxicol 5:1039-1048.
79. LeCluyse, E. L. (2001). Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur J Pharm Sci 13:343-368.
80. Li, N., Bi, Y. A., Duignan, D. B., Lai, Y. (2009). Quantitative expression profile of hepatobiliary transporters in sandwich cultured rat and human hepatocytes. Mol Pharmacol 6:1180-1189.
81. Lin, J. H., Lu, A. Y. H. (1998). Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharm 35:361-390. (Pubitemid 28520008)
82. Lindberg, P., Nordberg, P., Alminger, T., Brändström, A., Wallmark, B. (1986). The mechanism of action of the gastric acid secretion inhibitor omeprazole. J Med Chem 29:1327-1329. (Pubitemid 16034616)
83. Lipinski, C. A., Lombardo, F., Dominy, B. W., Feeney, P. J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3-25. (Pubitemid 27046991)
84. Luo, G., Johnson, S., Hsueh, M-M., Zheng, J., Cai, H., Xin, B., et al. (2010). In silico prediction of biliary excretion of drugs in rats based on physicochemical properties. Drug Metab Dis 38:422-430.
85. Mahmood, I. (1998). Interspecies scaling of renally secreted drugs. Life Sci 63:2365-2371.
86. Mahmood, I. (2005). Interspecies scaling of biliary excreted drugs: a comparison of several methods. J Pharm Sci 94:883-892.
87. Mazur, C. S., Kenneke, J. F., Goldsmith, M. R., Brown, C. (2009). Contrasting influence of NADPH and a NADPH-regenerating system on the metabolism of carbonyl-containing compounds in hepatic microsomes. Drug Metab Dispos 37:1801-1805.
88. McGinnity, D. F., Collington, J., Austin, R. P., Riley, R. J. (2007). Evaluation of human pharmacokinetics, therapeutic dose, and exposure predictions using marketed oral drugs. Curr Drug Metab 8:463-479. (Pubitemid 47603410)
89. McGinnity, DF, Zhang, G, Kenny, JR, Hamilton, GA, Otmani, S, Stams, KR, et al. (2009). Evaluation of multiple in vitro systems for assessment of CYP3A4 induction in drug discovery: human hepatocytes, pregnane X receptor reporter gene, and Fa2N-4 and HepaRG cells. Drug Metab Disp 37:1259-1268.
90. Miller, E. C., Miller, J. A. (1966). Mechanisms of chemical carcinogenesis: nature of proximate carcinogens and interactions with macromolecules. Pharmacol Rev 18:805-838.
91. Nassar, A. E., Kame, A. M., Clarimont, C. (2004). Improving the decision-making process in the structural modification of drug candidates: enhancing metabolic stability. Drug Dis Today 9:1020-1028.
92. Nelson, S. D., Pearson, P. G. (1990). Covalent and noncovalent interactions in acute lethal cell injury caused by chemicals. Ann Rev Pharmacol Toxicol 30:169-195.
93. Nestorov, I. A., Aarons, L. J., Arundel, P. A., Rowland, M. (1998). Lumping of whole-body physiologically based pharmacokinetic models. J Pharmaco Biopharm 26:21-46. (Pubitemid 28429460)
94. Obach, R. S., Walsky, R. L., Venkatakrishnan, K. (2007). Mechanism-based inactivation of human cytochrome P450 enzymes and the prediction of drug-drug interactions. Drug Met Disp 35:246-255. (Pubitemid 46148737)
95. Obach, R. S. (1999). Prediction of human clearance of twenty-nine drugs from hepatic microsomes intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350-1359.
96. Obach, R. S., Lombardo, F., Waters, N. J. (2008). Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab Dispos 36:1385-1405. (Pubitemid 351929323)
97. Oie, S., Tozer, T. N. (1979). Effect of altered plasma protein binding on apparent volume of distribution. J Pharm Sci 68:1203-1205. (Pubitemid 10231273)
98. Paine, S. W., Barton, P., Bird, J., Denton, R., Menochet, K., Smith, A., et al. (2010). A rapid computational filter for predicting the rate of human renal clearance. J Mol Graphics Mod 29:529-537.
99. Polli, J. W., Jarrett, J. J., Studenberg, S. D., Humphreys, J. E., Dennis, S. W., Brouwer, K. R., et al. (1999). Role of p-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 16:1206-1212. (Pubitemid 29393608)
100. Poulin, P., Theil, F. P. (2009). Development of a novel method for predicting human volume of distribution at steady-state of basic drugs and comparative assessment with existing methods. J Pharm Sci 98:4941-4961.
101. Poulin, P., Jones, H. M., Jones, R. D., Yates, J. W., Gibson, C. R., Chien, J. Y., et al. (2011). PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets. J Pharm Sci 2011 Apr 26. doi: 10.1002/jps.22554.
102. Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., et al. (2008). Prodrugs: design and clinical applications. Nat Rev Drug Discov 7:255-270. (Pubitemid 351324639)
103. Rawden, H. C., Carlile, D. J., Tindall, A., Halifax, D., Galetin, A., Ito, K., et al. (2005). Microsomal prediction of in vivo clearance and associated interindividual variability of six benzodiazepines in humans. Xenobiotica 35:603-625. (Pubitemid 41242917)
104. Read, K. D., Braggio, S. (2010). Assessing brain free fraction in early drug discovery. Expert Opin Drug Metab Toxicol 6:337-344.
105. Riley, R. J., Grime, K., Weaver, R. (2007). Time-dependent CYP inhibition. Expert Opin Drug Metab Toxicol 3:51-66. (Pubitemid 47315418)
106. Riley, R. J., McGinnity, D. F., Austin, R. P. (2005). A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metab Dispos 33:1304-1311. (Pubitemid 41196973)
107. Rodgers, T., Rowland, M. (2007). Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm Res 24:918-933. (Pubitemid 46675393)
108. Rowland, M., Tozer, T. N. (1989). Clinical pharmacokinetics: concepts and applications, 2nd ed. London: Lea and Febiger.
109. Rowland, M., Peck, C., Tucker, G. (2011). Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol 10:45-73.
110. Shitara, Y., Horie, T., Sugiyama, Y. (2006). Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci 27:425-446. (Pubitemid 43363338)
111. Sills, G. J., Kwan, P., Butler, E., de Lange, E. C. M., van den Berg, D-J., Brodie, M. J. (2002). P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice. Epil Behav 3:427-432. (Pubitemid 35460411)
112. Smith, D. A., Jones, B. C., Walker, D. K. (1996). Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Med Res Rev 16:243-266. (Pubitemid 26146807)
113. Smith, D. A. (2007). Do prodrugs deliver? Curr Opin Drug Discov Devel 10:550-559.
114. Smith, D. A., Di, L., Kerns, E. H. (2010). The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Disc 9:929-939.
115. Soars, M. G., Grime, K., Sproston, J. L., Webborn, P. J., Riley, R. J. (2007). Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo. Drug Metab Dispos 35:859-865. (Pubitemid 46798596)
116. Soars, M. G., Webborn, P. J., Riley, R. J. (2009). Impact of hepatic uptake transporters on pharmacokinetics and drug-drug interactions: use of assays and models for decision making in the pharmaceutical industry. Mol Pharmacol 6:1662-1677.
117. Sohlenius-Sternbeck, A-K., Jones, C., Ferguson, D., Middleton, B. J., Projean, D., Floby, E., et al. (2012). Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes. Xenobiotica 2012 Apr 18. doi: 10.3109/00498254.2012.669080.
118. Sun, H., Scott, D. O. (2010). Structure-based drug metabolism predictions for drug design. Chem Biol Drug Des 75:3-17.
119. Szakács, G., Váradi, A., Özvegy-Laczka, C., Sarkadi, B. (2008). The role of ABC transporters in drug absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox). Drug Disc Today 13:379-393.
120. Takahashi, M., Washio, T., Suzuki, N., Igeta, K., Yamashita, S. (2009). The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans. J Pharm Sci 98:4343-4353.
121. Tang, H., Mayersohn, M. (2011). Controversies in allometric scaling for predicting human drug clearance: an historical problem and reflections on what works and what does not. Curr Top Med Chem 11:340-350.
122. Tang, F., Horie, K., Borchardt, R. T. (2002). Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res 19:765-772. (Pubitemid 34686734)
123. Testa, B. (2009). Drug metabolism for the perplexed medicinal chemist. Chem Biodivers 6:2055-2070.
124. Thompson, R. A., Isin, E. M., Li, Y., Weaver, R., Weidolf, L., Wilson, I., et al. (2011). Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. Chem Biol Interac 19:65-71.
125. Tucker, G. T. (1981). Measurement of the renal clearance of drugs. Br J Clin Pharmacol 12:761-770.
126. Ungell, A-L., Nylander, S., Bergstrand, S., Sjöberg, Å., Lennernäs, H. (1998). Membrane transport of drugs in different regions of the intestinal tract of the rat. J Pharm Sci 87:360-366. (Pubitemid 28204591)
127. Ungell, A-L., Artursson, P. (2009). An overview of Caco-2 and alternatives for prediction of intestinal drug transport and absorption. In: van de Waterbeemd, H., Testa, B., (Eds.), Drug bioavailability: estimation of solubility, permeability, absorption and bioavailability, 2nd ed. (pp. 133-159). Weinheim, Germany: Wiley-VCH.
128. U.S. Food and Drug Administration. Guidance for industry: drug metabolism/drug interactions in the drug development process: studies in vitro. (1997). Available at: http://www.fda.gov/ downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm072104.pdf. Accessed on February 10, 2011.
129. U.S. Food and Drug Administration. (2006). Draft guidance for industry: drug interaction studies - study design, data analysis, and implications for dosing and labeling. Available at: http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm072101.pdf. Accessed on February 10, 2011.
130. U.S. Food and Drug Administration. (2008). Guidance for industry: safety testing of drug metabolites. Available at: http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm079266. pdf. Accessed on February 11, 2011.
131. Varma, M. V. S., Feng, B., Obach, R. S., Troutman, M. D., Chupka, J., Miller, H. R., et al. (2009). Physicochemical determinants of human renal clearance. J Med Chem 52:4844-4852.
132. van de Waterbeemd, H., Smith, D. A., Jones, B. C. (2001). Lipophilicity in PK design: methyl, ethyl, futile. J Comput Aided Mol Des 15:273-286.
133. Wan, H., Rehngren, M., Giordanetto, F., Bergström, F., Tunek, A. (2007). High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery. J Med Chem 50:4606-4615. (Pubitemid 47463235)
134. Ward, P. (2008). Importance of drug transporters in pharmacokinetics and drug safety. Toxicol Mech Methods 18:1-10.
135. Waring, M. J. (2009). Defining optimum lipophilicity and molecular weight ranges for drug candidates - molecular weight dependent lower logD limits based on permeability. Bioorg Med Chem Lett 19:2844-2851.
136. Waring, M. J. (2010). Lipophilicity in drug discovery. Expert Opin Drug Discov 5:235-248.
137. Wenlock, M. C., Austin, R. P., Barton, P., Davis, A. M., Leeson, P. D. (2003). A comparison of physiochemical property profiles of development and marketed oral drugs. J Med Chem 46:1250-1256. (Pubitemid 36428230)
138. Williams, J., Hyland, R., Jones, B., Smith, D., Hurts, S., Goosen, T., et al. (2004a). Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 32:1201-1208. (Pubitemid 39410902)
139. Williams, P. A., Cosme, J., Vinkovic, D. M., Ward, A., Angove, H. C., Day, P. J., et al. (2004b). Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 305:683-686. (Pubitemid 39006760)
140. Wu, C-Y., Benet, L. Z. (2005). Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22:11-23. (Pubitemid 40558141)
141. Yamashita, F., Hashida, M. (2004). In silico approaches for predicting ADME properties of drugs. Drug Met and Pharmaco. 19:327-338.
142. Yamazaki, M., Kobayashi, K., Sugiyama, Y. (1996). Primary active transport of pravastatin across the liver canalicular membrane in normal and mutant Eisai hyperbilirubinemic rats. Biopharm Drug Dispos 17:607-621. (Pubitemid 26319898)
143. Yang, X., Gandhi, Y. A., Duignan, D. B., Morris, M. E. (2009). Prediction of biliary excretion in rats and humans using molecular weight and quantitative structure-pharmacokinetic relationships. Am Assoc Pharm Sci J 11:511-525.
144. Yu, D. K. (1999). The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol 39:1203-1211.
145. Zhou, D., Afzelius, L., Grimm, S. W., Andersson, T. B., Zauhar, R. J., Zamora, I. (2006). Comparison of methods for the prediction of the metabolic site for CYP3A4-mediated metabolic reactions. Drug Metab Dis 34:976-983. (Pubitemid 43763754)
146. Zhou, S-F. (2008). Structure, function, and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 38:802-832.
147. Zhou, S-F. (2009a). Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet 48:689-723.
148. Zhou, S-F. (2009b). Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet 48:761-804.