Oxidation of drugs

Shimada, T. et al. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals studies with liver micro-somes of 30 Japanese and 30 Caucasians. /. Pharmacol. Exp. Ther., 270,414-23. 

Microbial oxidation of drug substrates occurs in a similar fashion to mammalian oxidative biotransformation. In contrast, microbial cultures rarely catalyze conjugations comparable to those in mammalian system (glucuronidation, sulfation and GSH conjugation). It is thus not surprising that microbial bioreactors are mainly used in the synthesis of oxidative metabolites. 

FIGURE 4.24 Hypochlorite -mediated oxidation of drugs associated with agranulocytosis to reactive metabolites. 

Uetrecht J. N-oxidation of drugs associated with idiosyncratic drug reactions. Drug Metab Rev 2002 34(3) 651-665. 

Gillette JR, Brodie BB, LaDue BN. 1957. The oxidation of drugs by liver microsomes On the role of TPHN and oxygen. J Pharmacol Exp Ther 119 532-540. 

Fig. 7.1 Heteroatom oxidation of drugs by cytochrome P450 leading to heteroatom oxides or dealkylation products. 

L. A. Damani, in N-Oxidation of Drugs. Biochemistry, Pharmacology, Toxicology (Eds. 

The primary enzymes responsible for the oxidation of drugs are located in the a cytoplasm... 

Similar to biologic oxidation, enzymatic oxidation of drugs opened a way to studies on the preparation of optically active sulfoxides by enzymatic procedures. Among numerous reports a typical example is the oxidation of aryl aminoalkyl sulfides by dopamine -hydoxylase (DBH) in Ae presence of some electron donors to afford the sulfoxide with high enantioselectivity (equation 54). °... 

Decomposition which probably involves the fission of a 10-substi-tuent with a three-carbon chain has however been observed upon photochemical oxidation of drugs. 

Monoamine oxidases (MAO-A and MAO-B) are mitochondrial enzymes that oxidatively deaminate endogenous biogenic amine neurotransmitters such as dopamine, serotonin, norepinephrine, and epinephrine. MAOs are like EMOs in that they catalyze the oxidation of drugs to produce drug metabolites that are identical in chemical structures to those formed by CYPs. Because the resulting structures are... 

Genetic factors account for some ADRs due to either altered pharmacokinetics or by altering tissue responsiveness. Altered metabolism of drugs occurs due to differences in hydrolysis, acetylation, and hepatic oxidation of drugs. Altered pharmacodynamic reactions could be either an exaggerated response or a... 

Extensive use has been tnade of semiempirieal methods in drug design. " Calculations of the highc.si occupied MO and lowe.st unoccupied MO IHOMO/LUMO) energies for a series of active and inactive compounds have been used as de.scriptors for QSAR. AMI. for example, has recently been used to develop a predictive ADME model for P-450 oxidation of drugs, which is di.scu.sscd below. 

One of the earliest demonstrations by ESR of the peroxidase oxidation of drugs involved the tranquilizer, chlorpromazine [171]. The stoichiometry of the reaction forming the chlorpromazine radical cation (13) was established, and kinetics of the transient radical were shown to be identical to those of an optically detected intermediate absorbing at 530 nm. Measurements were made of the pH-dependent radical dismutation rate and the rate of reaction of compound II with chlorpromazine. At high enzyme concentrations and low dismutation rates, the radical cation undergoes further oxidation by the enzyme, to form the thionium ion. 

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