Drug Metabolism in Drug Design and Development Basic Concepts and Practice
TABLE 16.1 LC–MS/MS analyses of individual CYP marker substrates in pooled human liver microsomes.CYPinvolved Substrate LC colum ...
Bufurarol BDS Hypersil C8, 5 m m, 2 50 mm 0–50% B 1.9 min linear (^01) -OH-Bufurarol278.1/186.1 DL -Propranolol260.2/155.1 CYP2E ...
substrate concentration profile using Michaelis–Menten equation (Eq. 16.1). Figure 16.1 shows the typical M–M kinetics of (S)-me ...
During the enzyme reaction of a substrate, multiple metabolite isomers may be formed. Thus, a baseline LC separation of the meta ...
2.5mL of the stock was dissolved in HLM working solution to appropriate concentrations. All working solutions were on ice before ...
16.2.6 Data Analysis Nonlinear curve fitting of enzyme kinetic data was accomplished with the Enzyme Kinetics module of either G ...
FIGURE 16.2 Methods to measureKivalues of competitive (a), noncompetitive (b), uncompetitive (c), and mixed type inhibition (d). ...
FIGURE 16.3 CYP inhibition curves of six known chemical inhibitors in the metabolism of marker substrates at theirKmvalues by hu ...
ForKidetermination, six various concentrations of the given substrate (spread aroundKm) and test compound (or known inhibitor, s ...
target enzyme is the substrate that in the process of catalytic turnover is metabolized to a reactive intermediate that inactiva ...
In comparison with the reversible enzyme inhibition, the MBI can be characterized to be (1) dose-dependent; (2) preincubation ti ...
where [E] is the active enzyme concentration at time t; [I] the inhibitor concentration,kinactthe inactivation rate constant, an ...
activity in 30 min (first order kinetics) is measured and apparent rate constant (kobs) can be obtained by an initial slope of t ...
known mechanism-based inhibitors ranged from 0.04 (ritonavir) to 108mM (rutaecarpine), and from 0.01 (diltiazem) to 1.62 min^1 ...
spectrometer to waste for the first and last minute of the gradient to remove nonvolatile salts. Mass to charge value for each m ...
interference. The fluorescent HTS comes with great sensitivity, simple operation, fast detection, lower expenditure, and quick t ...
16.5 PREDICTION OF HUMAN DRUG–DRUG INTERACTIONS FROM IN VITROCYP INHIBITION DATA When an enzyme inhibitor is identified to chang ...
inhibitor (usually [I]max,ss). If the drug elimination is due largely to a CYP (fm= 1), Equation 16.8 can be simplified to Equat ...
although the prediction of MBI-mediated DDIs is more complicated than that from reversible CYP inhibition (Brown et al., 2005; G ...
clinical observed DDIs. AUC½I AUCctr ¼ 1 þ kinactfu½I ðKIþfu½IÞkE ð 16 : 11 Þ If the CYP in gut contributes to the metabolism ...
«
23
24
25
26
27
28
29
30
31
32
»
Free download pdf
