Oxidation susceptible drugs

The drug designer must consider the susceptibility to, and consequences of, the principal Phase 1 metabolic reactions hydrolysis, reduction and oxidation. Susceptibility to oxidation can be calculated using semi-empirical molecular orbital theory. Ease of oxidation is reflected by the energy of the HOMO, and the probable site of oxidation can be predicted from calculation of the electrophilic superdelocalizability. Likewise, ease of reduction is related to LUMO energy, and probable site to nucleophilic superdelocalizability (Loew and Burt, 1990). 

G. Boccardi, Oxidative susceptibility texting. Chapter 7, in S. W. Baertschi (ed.). Pharmaceutical Stress Testing Predicting Drug Degradation, Vol. 153, Drugs and the Pharmaceutical Sciences, Taylor and Francis, 2005. 

Baertschi SW, Boccardi G (2005) Oxidative susceptibility testing. In Baertschi SW (ed) Pharmaceutical stress testing predicting drug degradation. Taylor Francis, Boca Raton. 

Isolation of LDL and Measurement of the Inhibition of LDL Oxidation. Blood samples were obtained from food-deprived cholesterol-fed rabbits with or without drug treatment. Plasma lipoproteins were isolated by discontinuous NaCl/KBr density gradient ultracentrifugation in a SW 50 Ti rotor (Beckman Instruments, Palo Alto, CA) for 20 h at 4°C. LDL was isolated in a density range of 1.019-1.063 g/mL, and was dialyzed extensively at 4 C under Nj against PBS (5 mM phosphate and 145 mM NaCl, pH 7.4) in darkness. LDL cholesterol was determined enzymatically. All samples were diluted in normal saline to give a final concentration of 150 mg/dL cholesterol for the oxidation susceptibility studies. 

It is important to state here that NMR techniques were used not only to characterize optimal lipid nanoparticles and liposomes for drug delivery but also helped to analyze the effects of drug therapy. As for example the lipoprotein profiles analyzed using a large population of subjects in response to fenofibrate therapy in dyslipidemic patients and to determine oxidation susceptibility of serum lipids as described by Tynkkynen et... 

An interesting aspect to CYP3A4-mediated drug oxidations is the susceptibility of the enzyme to exhibit a variety of atypical kinetic profiles including positive... 

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