Metabolic intermediate complex formation

Mayhew, B.S., Jones, D.R. and Hall, S.D. (2000) An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. Drug Metabolism and Disposition, 28 (9), 1031-1037. 

Chatterjee P, Franklin MR. Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenediox-yphenyl components. Drug Metab Dispos 2003 31(11) 1391-1397. 

Pershing L, Franklin MR. Cytochrome P-450 metabolic-intermediate complex formation and induction by macrolide antibiotics a new class of agents. Xenobiotica 1982 12 687-699. 

Jones DR, Ekins S, Li L, Hall SD (2007) Computational approaches that predict metabolic intermediate complex formation with CYP3A4 (+b5). Drug Metab Dispos 35 1466-1475... 

Sinai, C.J. and J.R. Bend (1995). Isozyme-selective metabolic intermediate complex formation of guinea pig hepatic cytochrome P450 by N-aralkylated derivatives of 1-aminobenzotriazole. Chem. Res. Toxicol. 8, 82-91. 

P450 3A4 Metabolic Intermediate Complex Formation and Time Dependent Inhibition... 

A number of reports also describe the prediction of mechanism-based inhibition (MBI) [17,18]. In this type of model, MBI is determined in part by spectral shift and inactivation kinetics. Jones et al. applied computational pharmacophores, recursive partitioning and logistic regression in attempts to predict metabolic intermediate complex (MIC) formation from structural inputs [17]. The development of models that accurately predict MIC formation will provide another tool to help reduce the overall risk of DDI [19]. 

Sharma U, Roberts ES, Hollenberg PF. Formation of a metabolic intermediate complex of cytochrome P4502B1 by clorgyline. Drug Metab Dispos 1996 24 1247-1253. 

Figure 3 MIC formation by diltiazem (5 pM) in HLMs. The sample cuvette contained HLMs, diltiazem, and NADPH, whereas the reference cuvette contained HLMs, buffer, and NADPH. The ribbons represent the change in absorbance difference for scans from 5 to 120 minutes. Abbreviations MIC, metabolic intermediate complex HLMs, human liver microsomes. Source From Ref. 37.

CYP3A4 is mainly responsible for catalyzing the hydro-xylation of miocamycin metabolites, which can alter the metabolism of concomitantly administered drugs by the formation of a metabolic intermediate complex with CYP450 or by competitive inhibition of CYP450 (25). This can cause excessive sedation with benzodiazepines such as triazolam. 

Figure 6 The structure of the potent quasi-irreversihle CYP3A4 inhibitor troleando-mycin (top panel), the metabolic steps required to convert troleandomycin into a nitroso metabolite that coordinates with the ferrous-heme of CYP3A4 (side panel), and the spectral changes associated with MI complex formation (bottom panel). Troleandomycin (50 pM) was incubated at 37°C with a human liver microsomal sample with high CYP3A4/5 activity (1 mg/mL) andNADPH (1 mM) for the times indicated. The reference cuvette contained the same components minus troleandomycin. Scans from 380 to 520 nm were recorded on a Varian Cary 100 BIO IJV/Vis dual beam spectrophotometer. Abbreviation MI, metabolic intermediate.

In contrast, metabolic sensors have the advantage to regenerate their affinity structures by themselves, because the substrate S is converted to the product P, which has a different affinity to the receptor, in this case an enzyme E. The response of enzyme-based sensors is induced by the production of P, and follows the Michaelis-Menten kinetics. The simplest case is the reversible formation of an. intermediate complex SE, which then decomposes with a velocity constant k to the product. The affinity constant in this case, called the Michaelis constant is an expression of the substrate concentration, at which half the maximum... 

Irreversible inhibition (mechanism-based inhibition, MBI) is among the most specific enzyme inhibitions, which includes CYP suicide inactivation process (the more widely studied process) and metabolite-intermediate complex (MI) formation (Silverman, 1995 Waley, 1980). The former involves metabolism of drugs to products that denature the CYP. In this case, the inactivator for the... 

The biosynthesis of threonine from aspartate involves formation of the four metabolic intermediates illustrated in Fig. 2. The /3-carboxyl group of aspartate is first activated by formation of an acylphosphate, and this reaction is followed by two reductive steps resulting in the synthesis of homoserine. After formation of a C4 phosphate ester of homoserine, threonine is synthesized by a complex rearrangement which entails formation of the terminal methyl group and transfer of the oxygen atom from C-4 to form a hydroxyl group at C-3. 

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