Drug metabolism in vitro

Trubetskoy, O.V., Gibson, J.R., and Marks, B.D. 2005. Highly miniaturized formats for in vitro drug metabolism assays using vivid fluorescent substrates and recombinant human cytochrome P450 enzymes. J. Biomol. Screen. 10 56. 

Wynalda, M.A., Hauer, M.J. and Wienkers, L.C. (1998) Human biotransformation of bropirimine. Characterization of the major bropirimine oxidative metabolites formed in vitro. Drug Metabolism and Disposition, 26 (10), 1048-1051. 

LC/MS/MS with selected reaction monitoring (SRM) offers a fast and simple means to analyze biological matrices, which is a key factor in high-throughput CYP inhibition screens using liver microsomes. Potentially, the LC/MS/MS technique is suitable for analyses of cocktail substrates in other in vitro drug metabolism evaluations such as CYP induction/activation assays, rapid analysis of pooled liver microsomes, rapid reaction phenotyping of tissue (hepatic and extrahepatic) samples, as well as evaluation of hepatocytes/tissue slice CYP activity. ° ... 

J. H. Beattie, L Joncour, K. et al. Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer. Rapid Commun Mass Spectrom 2005, 19, 843-848. 

P450 system In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Inducers or inhibitors of CYP3A4 may alter solifenacin pharmacokinetics. 

Madsen, K.G. et al. (2007) Development and evaluation of an electrochemical method for studying reactive phase-I metabolites correlation to in vitro drug metabolism. Chemical Research in Toxicology, 20 (5), 821-831. 

Kobayashi K., T. Ishizuka, N. Shimada, Y. Yoshimura, K. Kamijima, and K. Chiba (1999). Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metabolism and Disposition 27 763-766. 

Lu AYH, Huang S-M. In vitro drug metabolism studies during development of new drugs. In Sahajwalla C, ed. New Drug Development, New York Marcell Dekker, 2004 87-110. 

Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 1994 47 1469-1479. 

Kharasch ED, Whittington D, Hoffer C, et al. Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol importance of clinical investigations to validate in vitro drug metabolism studies. Clin Pharmacokinet 2005 44(7) 731-751. 

Dickinson et al. [38, 39] recently used (5)-warfarin and dextromethorphan as examples to demonstrate the value of incorporating mechanistic IVIVE models into population PK-PD models. Based on in vitro drug metabolism data and information on the frequency and activity of the different allelic forms of relevant CYPs, the statistical power of in vivo studies needed to discern the effect of genotypes on PK and PD was estimated. This approach represents a paradigm for assessing the impact of genetic polymorphisms on the PK and PD of new drugs prior to costly... 

Houston JB (1994) Relevance of in vitro kinetic parameters to in vivo metabolism of xenobiotics. Toxicol In vitro 8 507 Houston JB (1994) Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 47 1469... 

Hewitt, G.G., J. Perkins and S.A.M. Hotchkiss (2000). Metabolism of fluroxypyr, fluroxypyr methyl ester, and the herbicide fluroxypyr methylheptyl ester. I. During percutaneous absorption through fresh rat and human skin in vitro. Drug Metabol Disp., 28, 748-754. 

High-throughput in vitro drug metabolism assays... 

Measurement of pH or scintigraphy In vitro disintegration testing In vitro dissolution testing In vitro drug transport studies In vitro drug metabolism studies... 

In vitro drug metabolism including enzyme induction, metabolic stability. 

Microsomes isolated from hepatic tissue appear to retain all of the mixed-function oxidase capabilities of intact hepa-tocytes because of this, microsomal preparations (with the necessary cofactors, e.g.. NADPH. Mg- ) are u.scd frequently for in vitro drug metabolism studies. Because of its membrane-bound nature, the cytochrome P-450 monooxy-gena.se system appears to be housed in a lipoidal environment. This may explain, in part, why lipophilic xenobiotics arc generally good sub.straics for the monooxygenase system. ... 

Table 5-6. A comparison of the key in vitro drug-metabolizing experimental systems in their contents of the major drug-metabolizing enzymes)...

In vitro Drug Metabolism Studies Guiding Early Drug Safety Evaluations 551... 

This diagram is not a comprehensive guide to drug discovery. However, it does show that the chemists discover new chemical entities with desirable properties. In vitro biochemistry is followed by initial in vivo work in the rat which is conducted with pharmacokinetic support and in vitro drug metabolism in parallel. Compounds meeting pre-arranged criteria proceed through... 

PJ Eddershaw, M Dickins. Advances in in vitro drug metabolism screening. Pharm Sci Technol Today 2 13—19, 1999. 

Houston JB, Carlile DJ (1997) Incorporation of in vitro drug metabolism data into physiologically- based pharmacokinetic models. Toxicol In Vitro 11(5) 473M78... 

Eddershaw, P.J. Dickens, M. Advances in In Vitro Drug Metabolism Screening, Pharm. Sci. Technol. Today 2(1), 13-19(1999). 

In vitro drug metabolism and in vitro drug-drug interaction studies and possible... 

---