Drug Metabolism in Drug Design and Development Basic Concepts and Practice
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8 DRUG METABOLISM RESEARCH AS AN INTEGRAL PART OF THE DRUG DISCOVERY PROCESS W. GRIFFITHHUMPHREYS 8.1 INTRODUCTION Drug metaboli ...
(1) a decreased clearance may translate into a lower overall dose; (2) lower rates of formation and overall amounts of reactive ...
concerns do arise, there are several avenues discussed below that can be followed to isolate the factor(s) limiting the oral del ...
concentration of most drugs is closer to the total plasma concentration than the free plasma concentration due to efficient upta ...
Alternatively, bile and urine metabolites can be estimated with HPLC–UV chromatography using the extinction coefficient of the p ...
results (Fig. 8.1). Systematic decision trees can be employed to allow clear pathways for evaluation of new compounds. Alternati ...
been published to date fall into four categories: (1) expert systems designed to identify probable sites of metabolism based on ...
8.4 Reaction Phenotyping It is extremely important to gain an early understanding of the enzymes predicted to be important for m ...
with glucuronic acid or acyl coenzyme A are also thought to be a source of reactive metabolites. The study of the interaction of ...
bind cellular macromolecules. Although there are many literature values for covalent binding of compounds associated with toxici ...
8.5.3 Toxicology Mediated Through Metabolite Interaction with Off-Target Receptors The biotransformation of parent molecules oft ...
During lead optimization, drug candidates are routinely screened for metabolic stability orin vivosystemic exposure and rank ord ...
the effect will be dramatically different in humans unless similar levels of metabolite can be expected in humans. An active met ...
However, this approach requires significant ‘‘deconvolution’’ efforts when activity is found in mixtures. To increase the succes ...
is to take samples of interest (i.e, microsomal incubations, plasma samples) and isolate and purify any metabolites present, aft ...
Also, medium-throughput screens for bioavailability are now possible with rapid quantitation by LC–MS/MS techniques. These techn ...
de Groot MJ, Ekins S. Pharmacophore modeling of cytochromes P450. Adv Drug Deliv Rev 2002;54:367–383. Dieckhaus CM, Fernandez-Me ...
Guengerich FP. Cytochrome P450S and other enzymes in drug metabolism and toxicity. AAPS J 2006;8:E101–E111. Hawkins DR. Use and ...
Lewis DF. Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes. To ...
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