Metabolic intermediate complexes

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. 

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]. 

Liquid chromatography/ultraviolet detection Monoamine oxidase Mechanism-based inhibition Metabolic intermediate complex Molybdenum-containing oxidase Multi parameter optimization... 

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.

Franklin R. Inhibition of mixed-function oxidations by substrates forming reduced cytochrome P-450 metabolic-intermediate complexes. Pharmacol Ther 1977 2 227-245. 

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... 

A number of classes of monooxygenase inhibitors, in addition to methylene-dioxyphenyl compounds, are now known to form metabolic-intermediate complexes including amphetamine and its derivatives and SKF-525A and its derivatives. 

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. 

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. 

A metabolic intermediate complex (MIC) observed only with CYP3A4 but not CYPs 3A5 and 3A7. 

C, competitive inhibition through P450 Fe /Fe" -heme complexation MBI, Mechanism-based inactivation that is either quasi-irreversible (QI) via metabolic intermediate complexation or irreversible (suicidal, S). 

Franklin, M.R. (1991). Cytochrome P450 metabolic intermediate complexes from macrolide antibiotics and related compounds. Meth. Enzymol. 206, 559-573. 

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

Cemy MA, Hanzlik RP (2005) Cyclopropylamine inactivation of cytochromes P450 role of metabolic intermediate complexes. Arch Biochem Biophys 436 265-275... 

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