In vitro ADME phenotyping in drug discovery: Current challenges and future solutions

Current Opinion in Drug Discovery and Development

Volumn 8, Issue 1, 2005, Pages 78-88

  Williams, J Andrew ^a   Bauman, Jonathan ^a   Cai, Hongliang ^a   Conlon, Kevin ^a   Hansel, Steven ^a   Hurst, Susan ^a   Sadagopan, Nalini ^a   Tugnait, Meera ^a   Zhang, Liming ^a   Sahi, Jasminder ^a  

^a PFIZER INC   (United States)

Author keywords

ADME; Drug discovery abstract; Drug metabolizing enzymes; Drug transporters; Phenotyping

Indexed keywords

AMFEBUTAMONE; AZAMULIN; CI 1027; CYCLOPHOSPHAMIDE; CYTOCHROME P450 3A4; DIFLOMOTECAN; DIGOXIN; ESTRADIOL; FLAVONOID; FLURBIPROFEN; GLUCURONOSYLTRANSFERASE 1A1; KETOCONAZOLE; LOPERAMIDE; NORMEPHENYTOIN; PHENOBARBITAL; PRAVASTATIN; PYRROLE DERIVATIVE; RIFAMPICIN; SEROTONIN; TETRYLAMMONIUM; THIOTEPA; TICLOPIDINE; UNCLASSIFIED DRUG;

DECISION MAKING; DRUG ABSORPTION; DRUG DETERMINATION; DRUG DISPOSITION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG EXCRETION; DRUG METABOLISM; DRUG SAFETY; DRUG TISSUE LEVEL; DRUG TRANSPORT; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PHARMACODYNAMICS; PHARMACOGENOMICS; PHENOTYPE; REVIEW; TECHNOLOGY;

ANIMALS; CARRIER PROTEINS; COMPUTER SIMULATION; ENZYMES; HUMANS; PHARMACEUTICAL PREPARATIONS; PHARMACOGENETICS; PHENOTYPE;

EID: 19944428787     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (73)

1. Williams JA, Hurst SI, Bauman J, Jones BC, Hyland R, Gibbs JP, Obach RS, Ball SE: Reaction phenotyping in drug discovery: Moving forward with confidence? Curr Drug Metab (2003) 4(6):527-534. Provides a detailed review of methodology for drug metabolism reaction phenotyping in the absence of radiolabel or metabolite standards.
2. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G et al: The conduct of in vitro and in vivo drug-drug interaction studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos (2003) 31(7):815-832. Provides a definitive position of the state-of-the-art in DDI studies.
3. Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, Ball SE: Drug-drug interactions for UGT substrates: A pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos (2004) 32(11):1201-1208. Description of the basis for predicting the magnitude of DDIs from in vitro data using pharmacokinetic principles, including a review of clearance mechanisms for the top 200 drugs prescribed in the US in 2002.
4. Hyland R, Jones BC, Smith DA: Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos (2003) 31(5):540-547.
5. Bauman J, Goosen TC, Hurst SI, Tugnait M, Williams JA: UGT reaction phenotyping for CI-1027. Drug Metab Rev (2004) 36:132.
6. Lesko LJ, Salemo RA, Spear BB, Anderson DC, Anderson T, Brazell C, Collins J, Domer A, Essayan D, Gomez-Mancilla B, Hackett J et al: Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: Report of the first FDA-PWG-PhRMA-DruSafe Workshop. J Clin Pharmacol (2003) 43(4):342-358.
7. Salerno RA, Lesko LJ: Pharmacogenomic data: FDA voluntary and required submission guidance. Pharmacogenomics (2004) 5(5):503-505. Provides guidance on submission of ADME pharmacogenomic data to the FDA.
8. Williams JA, Cook J, Hurst SI: A significant drug-metabolizing role for CYP3A5? Drug Metab Dispos (2003) 31(12):1526-1530.
9. i and dangers associated with high clearance drugs in general. J Pharm Pharm Sci (1999) 2(2):47-52.
10. Flockhart DA: Drug interactions, cardiac toxicity and terfenadine: From bench to clinic? J Clin Psychopharmacol (1996) 16(2):101-103.
11. Hirota N, Ito K, Iwatsubo T, Green CE, Tyson CA, Shimada N, Suzuki H, Sugiyama Y: In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans. Biopharm Drug Dispos (2001) 22(2):53-71.
12. Venkatakrishnan K, von Moltke LL, Greenblatt DJ: Application of the relative activity factor approach in scaling from heterologously expressed cytochromes P450 to human liver microsomes: Studies on amitriptyline as a model substrate. J Pharmacol Exp Ther (2001) 297(1):326-337.
13. Turpeinen M, Nieminen R, Juntunen T, Taavitsainen P, Raunio H, Pelkonen O: Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos (2004) 32(6):626-631.
14. Cai X, Wang RW, Edom RW, Evans DC, Shou M, Rodrigues AD, Liu W, Dean DC, Baillie TA: Validation of (-)-N-3-benzyl-phenobarbital as a selective inhibitor of CYP2C19 in human liver microsomes. Drug Metab Dispos (2004) 32(6):584-586.
15. Walsky RL, Obach RS: Verification of the selectivity of (+)-N-3-benzylnirvanol as a CYP2C19 inhibitor. Drug Metab Dispos (2003) 31(3):343.
16. Stresser DM, Broudy MI, Ho T, Cargill CE, Blanchard AP, Sharma R, Dandeneau AA, Goodwin JJ, Turner SD, Erve JC, Patten CJ et al: Highly selective inhibition of human CYP3Aa in vitro by azamulin and evidence that inhibition is irreversible. Drug Metab Dispos (2004) 32(1):105-112.
17. Rae JM, Soukhova NV, Flockhart DA, Desta Z: Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: Implications for cyclophosphamide metabolism. Drug Metab Dispos (2002) 30(5):525-530.
18. Klotz U, Schwab M, Treiber G: CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol (2004) 95(1):2-8.
19. Williams JA, Ring BJ, Cantrell VE, Campanale K, Jones DR, Hall SD, Wrighton SA: Differential modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed estradiol-3-glucuronidation by the addition of UGT1A1 substrates and other compounds to human liver microsomes. Drug Metab Dispos (2002) 30(11):1266-1273.
20. Sridar C, Goosen TC, Kent UM, Williams JA, Hollenberg PF: Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos (2004) 32(6):587-594.
21. Goosen TC, Arimoto R, Gifford E, Ball SE, Hurst SI, Tugnait M, Hollenberg PF, Williams JA: A computational model based on UGT1A inhibition in human liver microsomes predicts the tacrolimus-mycophenolic acid metabolic drug interaction. Drug Metab Rev (2003) 35:58.
22. Senafi SB, Clarke DJ, Burchell B: Investigation of the substrate specificity of a cloned expressed human bilirubin UDP-glucuronosyltransferase: UDP-sugar specificity and involvement in steroid and xenobiotic glucuronidation. Biochem J (1994) 303 (Pt 1):233-240.
23. Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, Greenblatt DJ: Evaluation of 3′-azido-3′-deoxythymidine, morphine and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: Specificity and influence of the UGT2B7*2 polymorphism. Drug Metab Dispos (2003) 31(9):1125-1133. Demonstrates an approach for the reaction phenotyping of UDP-glucuronosyltransferase 2B7 substrates.
24. Foti RS, Fisher MB: Impact of incubation conditions on bufuralol human clearance predictions: Enzyme lability and nonspecific binding. Drug Metab Dispos (2004) 32(3):295-304.
25. Bachmann K, Byers J, Ghosh R: Prediction of in vivo hepatic clearance from in vitro data using cryopreserved human hepatocytes. Xenobiotica (2003) 33(5):475-483.
26. Johnson TN, Sabzghabaee A, Rostami-Hodjegan A, Tucker GT: Prediction of age related changes in midazolam clearance in children using simcyp. Br J Clin Pharmacol (2003) 55:432-433. Discusses the application of a predictive tool using in vitro CYP phenotyping data.
27. Proctor NJ, Tucker GT, Rostami-Hodjegan A: Predicting drug clearance from recombinantly expressed CYPs: Intersystem extrapolation factors. Xenobiotica (2004) 34(2):151-178.
28. Abian J, Oosterkamp AJ, Gelpi E: Comparison of conventional, narrow-bore and capillary liquid chromatography/mass spectrometry for electrospray ionization mass spectrometry: Practical considerations. J Mass Spectrom (1999) 34:244-254.
29. Kostiainen R, Kotiaho T, Kuuranne T, Auriola S: Liquid chromatography/atmospheric pressure ionization-mass spectrometry in drug metabolism studies. J Mass Spectrom (2003) 38(4):357-372.
30. Hopfgartner G, Bourgogne E: Quantitative high-throughput analysis of drugs in biological matrices by mass spectrometry. Mass Spectrom Rev (2003) 22(3):195-214.
31. Su Y, Lee SH, Sinko PJ: Practical aspects of transporter model systems: A case study involving SQV. Drug Metab Rev (2004) 36(2):377-389.
32. Ayrton A, Morgan P: Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica (2001) 31(8-9):469-497. Landmark paper describing the role of drug transporters.
33. Benet LZ, Cummins CL, Wu CY: Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm (2004) 277(1-2):3-9.
34. Schwarz UI, Gramatte T, Krappweis J, Oertel R, Kirch W: P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans. Int J Clin Pharmacol Ther (2000) 38(4):161-167.
35. Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G: Predicting P-glycoprotein effects on oral absorption: Correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a (-/-) mice in vivo. Pharm Res (2004) 21(5):819-826.
36. Sadeque AJ, Wandel C, He H, Shah S, Wood AJ: Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther (2000) 68(3):231-237.
37. Bednarczyk D, Ekins S, Wikel JH, Wright SH: Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1. Mol Pharmacol (2003) 63(3):489-498.
38. Verrey F, Meier C, Rossier G, Kuhn LC: Glycoprotein-associated amino acid exchangers: Broadening the range of transport specificity. Pflugers Arch (2000) 440(4):503-512.
39. Koepsell H: Organic cation transporters in intestine, kidney, liver and brain. Annu Rev Physiol (1998) 60:243-266.
40. Drescher S, Glaeser H, Murdter T, Hitzl M, Eichelbaum M, Fromm MF: P-glycoprotein-mediated intestinal and biliary digoxin transport in humans. Clin Pharmacol Ther (2003) 73(3):223-231.
41. Sparreboom A, Gelderblom H, Marsh S, Ahluwalia R, Obach R, Principe P, Twelves C, Verweij J, McLeod HL: Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype. Clin Pharmacol Ther (2004) 76(1):38-44.
42. Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, Kyrklund C, Backman JT, Kerb R, Schwab M, Neuvonen PJ, Eichelbaum M et al: High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics (2004) 14(7):429-440. Example of an approach to quantitatively measure transporter polymorphism effects in humans.
43. Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH: Deficiency in the organic cation transporters 1 and 2 (OCT1/OCT2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol (2003) 23(21):7902-7908. Demonstrates the potential of genetically modified mouse models to predict the in vivo role of drug transporters.
44. Piyapolrungroj N, Li C, Bockbrader H, Liu G, Fleisher D: Mucosal uptake of gabapentin (neurontin) vs pregabalin in the small intestine. Pharm Res (2001) 18(8):1126-1130.
45. Sakaeda T, Nakamura T, Okumura K: Pharmacogenetics of drug transporters and its impact on the pharmacotherapy. Curr Top Med Chem (2004) 4(13):1385-1398.
46. Kusuhara H, Sugiyama Y: Role of transporters in the tissue-selective distribution and elimination of drugs: Transporters in the liver, small intestine, brain and kidney. J Control Release (2002) 78(1-3):43-54.
47. Faber KN, Muller M, Jansen PL: Drug transport proteins in the liver. Adv Drug Deliv Rev (2003) 55(1):107-124.
48. Hirano M, Maeda K, Shitara Y, Sugiyama Y: Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther (2004) 311(1):139-146. Describes the prediction of relative contributions of transporters to hepatic uptake in vivo from in vitro data.
49. Eraly SA, Bush KT, Sampogna RV, Bhatnagar V, Nigam SK: The molecular pharmacology of organic anion transporters: From DNA to FDA? Mol Pharmacol (2004) 65(3):479-487.
50. Lee W, Kim RB: Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol (2004) 44:137-166.
51. Hackbarth H, Buttner D, Gartner K: Intraspecies allometry: Correlation between kidney weight and glomerular filtration rate vs body weight. Am J Physiol (1982) 242(3):R303-R305.
52. Mahmood I: Interspecies scaling of renally secreted drugs. Life Sci (1998) 63(26):2365-2371.
53. Mankowski DC, Lawton MP, Ekins S: Characterization of transgenic mouse strains using six human hepatic cytochrome P450 probe substrates. Xenobiotica (2000) 30(8):745-754. Provides a comparison of drug metabolizing activities in genetically modified mouse models.
54. Obach RS: Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos (1999) 27(11):1350-1359.
55. Beresford AP, Segall M, Tarbit MH: In silico prediction of ADME properties: Are we making progress? Curr Opin Drug Discovery Dev (2004) 7(1):36-42.
56. Lombardo F, Gifford E, Shalaeva MY: In silico ADME prediction: Data, models, facts and myths. Mini Rev Med Chem (2003) 3(8):861-875.
57. Darvas F, Keseru G, Papp A, Dorman G, Urge L, Krajcsi P: In silico and ex silico ADME approaches for drug discovery. Curr Top Med Chem (2002) 2(12):1287-1304.
58. de Groot MJ, Ekins S: Pharmacophore modeling of cytochromes P450. Adv Drug Deliv Rev (2002) 54(3):367-383.
59. Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther (1999) 291(1):424-433.
60. Ekins S, Stresser DM, Williams JA: In vitro and pharmacophore insights into CYP3A enzymes. Trends Pharmacol Sci (2003) 24(4):161-166.
61. Lewis DF, Modi S, Dickins M: Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev (2002) 34(1-2):69-82.
62. Masimirembwa CM, Ridderstrom M, Zamora I, Andersson TB: Combining pharmacophore and protein modeling to predict CYP450 inhibitors and substrates. Methods Enzymol (2002) 357:133-144.
63. Riley RJ, Parker AJ, Trigg S, Manners CN: Development of a generalized, quantitative physicochemical model of CYP3A4 inhibition for use in early drug discovery. Pharm Res (2001) 18(5):652-655.
64. Williams PA, Cosme J, Vinkovic DM, Ward A, Angove HC, Day PJ, Vonrhein C, Tickle IJ, Jhoti H: Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science (2004) 305(5684):683-686.
65. Yano JK, Wester MR, Schoch GA, Griffin KJ, Stout CD, Johnson EF: The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05-Å resolution. J Biol Chem (2004) 279(37):38091-38094.
66. Miners JO, Smith PA, Sorich MJ, McKinnon RA, Mackenzie PI: Predicting human drug glucuronidation parameters: Application of in vitro and in silico modeling approaches. Annu Rev Pharmacol Toxicol (2004) 44:1-25. Discusses emerging data on QSAR for substrates of UGTs.
67. de Groot MJ, Alex AA, Jones BC: Development of a combined protein and pharmacophore model for cytochrome P450 2C9. J Med Chem (2002) 45(10):1983-1993.
68. Smith PA, Sorich MJ, Low LS, McKinnon RA, Miners JO: Towards integrated ADME prediction: Past, present and future directions for modelling metabolism by UDP-glucuronosyltransferases. J Mol Graph Model (2004) 22(6):507-517.
69. Rios GR, Tephly TR: Inhibition and active sites of UDP- glucuronosyltransferases 2B7 and 1A1. Drug Metab Dispos (2002) 30(12):1364-1367.
70. Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan LB, Yasuda K, Shepard RL, Winter MA, Schuetz JD, Wikel JH et al: Application of three-dimensional quantitative structure-activity relationships of P-glycoprotein inhibitors and substrates. Mol Pharmacol (2002) 61(5):974-981. Demonstrates the emerging understanding of QSARs for substrates of the most-studied drug transporter.
71. Dierks EA, Stams KR, Lim HK, Cornelius G, Zhang H, Ball SE: A method for the simultaneous evaluation of the activities of seven major human drug-metabolizing cytochrome P450s using an in vitro cocktail of probe substrates and fast gradient liquid chromatography tandem mass spectrometry. Drug Metab Dispos (2001) 29(1):23-29.
72. Sahi J, Milad MA, Zheng X, Rose KA, Wang H, Stilgenbauer L, Gilbert D, Jolley S, Stern RH, LeCluyse EL: Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor. J Pharmacol Exp Ther (2003) 306(3):1027-1034.
73. Mills JB, Rose KA, Sadagopan N, Sahi J, de Morais SM: Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J Pharmacol Exp Ther (2004) 309(1):303-309.