Drug Metabolism in Drug Design and Development Basic Concepts and Practice

interindividual variability in exposure via significant drug–drug interactions or polymorphic expression coupled with the advanc ...

15.2 Cytochrome P450 Reaction Phenotyping Many enzyme systems exist that can contribute to the clearance of drugs from the syste ...

chapter, it is important to generally consider the concentration of NCE, the nature of the buffer system, the tolerance level of ...

15.3 Noncytochrome P450 Reaction Phenotyping Similar to P450 reaction phenotyping, designing experimental studies to elucidate t ...

Multiple FMO-3 variants have been identified. The best studied relationship between FMO-3 polymorphisms and enzyme function is t ...

the mitochondial and microsomal subcellular fractions. Since the oxidative enzymatic activities were highly correlated between t ...

of irinotecan was further evaluated by enzyme kinetic studies using purified hCE-1 and hCE-2 and bioactivation studies with puri ...

Understanding of genetic influence on pharmacokinetic variability for drugs primarily cleared by glucuronidation has advanced mo ...

expression levels of individual UGTs in human tissues and in individual preparations of recombinant enzymes. To date, attempts t ...

Preliminary assessment of kinetics in human liver microsomes (Step 1) revealed an S 50 of approximately 1 mM, which was the conc ...

variability in pharmacokinetics observed for isoniazid. Recombinant forms of these enzymes are commercially available, and human ...

15.6 Nonradiolabeled Reaction Phenotyping For the purposes of definition, nonradiolabeled reaction phenotyping is that conducted ...

metabolic turnover between individual enzymes, and the identification of metabolites formed by individual enzymes. Additionally, ...

Hepatic cytosol is a useful source of sulfotransferases (Pacifici, 2004) and aldehyde oxidase (Lake et al., 2002). Compared with ...

than compounds with much higher Kms. Compounds primarily cleared by glucuronidation typically have highKms, and therefore rarely ...

period, it will not be possible to define the relative contributions of each enzyme. This presents a decision point on whether t ...

of consistency, amounts of enzyme should be normalized to equivalent amounts of nanomole P450 per incubation (Williams et al., 2 ...

(e.g., NADPH). The concentration of solvents, particularly methanol and DMSO, should be kept to a minimum (see Section 15.2). Re ...

addition to the five major listed cytochrome P450s (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A), the other listed inhibitors inc ...

15.6.4.3 Correlation Analysis A human liver bank phenotyped for cyto- chrome P450 activities (and potentially UGT activities) ca ...