A hierarchical screening methodology for physicochemical/ADME/Tox profiling

Expert Opinion on Drug Metabolism and Toxicology

Volumn 2, Issue 5, 2006, Pages 805-817

  DeWitte, Robert S ^a   Robins, Russell H ^b  

^a Thermo Fisher Scientific   (United States)

^b PFIZER INC   (United States)

Author keywords

ADME Tox; Automation; CYP inhibition; Informatics; LogP; Metabolic stability; PADMET; Protein binding; Screening; Software; Solubility

Indexed keywords

AUTOMATION; COMPUTER PROGRAM; DECISION MAKING; DRUG MANUFACTURE; ENZYME INHIBITION; PHYSICAL CHEMISTRY; PROTEIN BINDING; REVIEW; SCREENING; SYNTHESIS;

AUTOMATION; CHEMISTRY, PHARMACEUTICAL; COMPUTER SIMULATION; CYTOCHROME P-450 ENZYME SYSTEM; DIMETHYL SULFOXIDE; DRUG EVALUATION, PRECLINICAL; DRUG INTERACTIONS; DRUG TOXICITY; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS; SOLUBILITY; TECHNOLOGY, PHARMACEUTICAL;

EID: 33846269351     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425255.2.5.805     Document Type: Review

References (21)

1. MACCOSS M, BAILLIE TA: Organic chemistry in drug discovery. Science (1994) 303:1810-1813. A prospective analysis of the changing role of the medicinal chemist in drug discovery research.
2. SAUNDERS KC: Automation and robotics in ADME Screening. Drug Discovery Today: Technologies (1994) 1:373-380. A thorough review of various approaches to laboratory automation for ADME applications.
3. POPA-BURKE I, ISSAKOVA O, ARROWAY JD et al.: Streamlined system for purifying and quantifying a diverse library of compounds and the effect of compound concentration measurements on the accurate interpretation of biological assay results. Anal. Chem. (2004) 76:7278-7287. A seminal paper exposing the extent of solubility related issues in high throughput analysis of DMSO samples.
4. MARGOLIS JM, OBACH RS: Impact of non-specific binding to microsomes and phospholipid on the inhibition of cutochrome P4502D6: implications for relating in vitro inhibition data to in vivo drug interactions. Drug Metab. Dispos. (2003) 31:606-611. Highlights the magnitude of the effect of nonspecific binding on ADME results.
5. GIULIANO C, JAIRAJ M, ZAFIU CM, LAUFER R: Direct determination of unbound intrinsic drug clearance in the microsomal stability assay. Drug Metab. Dispos. (2005) 33:1319-1324. A technique for removing bias due to nonspecific binding.
6. LOVAN K: High throughput drug-drug interaction assay: comparison of LeadStream with a semi-automated approach. Society of Biomolecular Screening, Geneva, Switzerland (2005):P0525.
7. HAAS H: High throughput metabolic stability assays: comparison of LeadStream with a semi-automated approach. Society of Biomolecular Screening, Geneva, Switzerland (2005):P0527.
8. DEWITTE RS: LeadStream performance characteristics over hundreds of compounds across multiple assays. Society of Biomolecular Screening, Geneva, Switzerland (2005):P0524.
9. BURDETTE D: Rational robotics for ADMET screening. LabAutomation 2005. San Jose, CA, USA (2005). Provides an analysis of where time and money are spent in the ADME screening process.
10. PENG SX, BRANCH TM, KING SL: Fully automated liquid-liquid extraction for analysis of biological samples by liquid chromatography with tandem mass spectrometry. Anal. Chem. (2001) 73:708-714.
11. BEVAN CD, LLOYD RS: A high-throughput screening method for the determination of aqueous drug solubility using laser nephelometry in microtiter plates. Anal. Chem. (2000) 72:1781-1787.
12. STOPHER D, MCCLEAN S: An improved method for the determination of distribution coefficients. J. Pharm. Pharmacol. (1990) 42:144.
13. LOMBARDO F, SHALAEVA MY, TUPPER KA, GAO F, ABRAHAM MH: ElogPoct: a tool for lipophilicity determination in drug discovery. J. Med. Chem. (2001) 43:2922-2928.
14. COHEN LH, REMLEY MJ, RAUNIG D, VAZ AD: In vitro drug interactions of cytochrome P450: an evaluation of fluorogenic to conventional substrates. Drug Metab. Dispos. (2003) 31:1005-1015.
15. JANISZEWSKI J, ROGERS KJ, WHALEN KM et al.: A high-capacity LC/MS system for the bioanalysis of samples generated from plate-based metabolic screening. Anal. Chem. (2001) 73:1495-1501.
16. KORFMACHER WA, PALMER CA, NARDO C et al.: Development of an automated mass spectrometry system for the quantitative analysis of liver microsomal incubation samples: a tool for rapid screening of new compounds for metabolic stability. Rapid Commun. Mass Spectrom. (1999) 13:901-907.
17. AYRTON J, PLUMB R, LEAVENS WJ, MALLETT D, DICKINS M, DEAR GJ: Application of a fast gradient liquid chromatography tandem mass spectrometry method for the analysis of cytochrome PO450 probe substrates. Rapid Commun. Mass Spectrom. (2001) 12:217-224.
18. KERNS EH: High throughput physicochemical profiling for drug discovery. J. Pharm. Sci. (2001) 90:1838-1858.
19. JENKINS KM, ANGELES R, QUINTOS MT, XU R, KASSEL DB, ROURICK RA: Automated high throughput ADME assays for metabolic stability and cytochrome P450 inhibition profiling of combinatorial libraries. J. Pharm. Biomed. Anal. (2004) 34:989-1004.
20. ROBINS RH: Case study of PADMET automation approaches. Drug Discovery Technology 2005. Boston, MA, USA (2005).
21. http://www.acdlabs.com/download/app/phys chem/sds.pdf BHAL S, KASSAM K: Structure optimization of leads to improve ADME properties. ACD/Labs application note (2006).