0-Dealky lation

Karim et al determined that the main pathway of disopyramide metabolism involved N-dealky-lation of the isopropyl group and arylhydroxy-lation, with a marked species difference in biotransformation between dog, rat, and man. 

Many xenobiotics contain alkyl groups, such as the methyl (-CH3) group, attached to atoms of O, N, and S. An important step in the metabolism of many of these compounds is replacement of alkyl groups by H, as shown in Figure 7.6. These reactions are carried out by mixed-function oxidase enzyme systems. Examples of these kinds of reactions with xenobiotics include O-dealky-lation of methoxychlor insecticides, N-dealkylation of carbary 1 insecticide, and S-dealkylation of dimethyl mercaptan. Organophosphate esters (see Chapter 18) also undergo hydrolysis, as shown in Reaction 7.3.12 for the plant systemic insecticide demeton ... 

A microsomal enzyme system catalyses -dealkylation with oxidative removal of the alkyl group to yield the corresponding aldehyde, as with TV-dealky lation (figure 4,16). However, as there are certain differences from the TV-dealkylation reaction it has been suggested that another enzyme system, such as the microsomal FAD-containing monooxygenase system may be involved. 

Activation energy of metabolism reactions with eflective atomic descriptors Training molecules not described (394 metabolic sites for aliphatic hydroxylation, 27 for A-dealky-lation, 9 for O-dealkylation, 85 for aromatic hydroxylation). N = 46 CYP3A4 substrates. Regioselectivity predictions 60% correct. 205... 

Cinnarizine, antihistamine. Rat. Extensively metabolized. N-dealky-lation (M), metabolite (benzhydrol) in urine as glue. N-oxidation (m). 

In the presence of NADPH and oxygen, hepatic microsomal enzymes convert the following substrates to the corresponding N-oxides chlorpromazine, chlor-qrclizine. imipramine. nicotinamide, guanethidine, and trimethylamine. Based on limited data, it was sug sted that the formation of N-oxides might be an intermediate step in all microsomal N-dealkylations. It is now clear that although N-oxides are formed by liver microsomes, they are not obligatory intermediates in all N-dealky-lation reactions. 

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