Polar compounds paradox

Biotransformation of certain chlorinated hydrocarbon insecticides results in their conversion to metabolites which are less polar than the parent chemical. Heptachlor and aldrin are converted to the more lipophilic compounds heptachlor epoxide and dieldrin, respectively, whereas DDT is converted to DDE. The primary residue of DDT, which persists to the present day in animals and humans after exposure over a decade ago, is DDE. Following biotransformation, these compounds distribute to tissues which are higher in neutral lipid content than are the major organs of metabolism and excretion, the liver and kidney. These lipid-rich tissues are relatively, deficient in the so-called mixed-function oxidase (MFO) enzyme systems necessary for biotransformation of the halogenated hydrocarbons to more polar and thus more easily excreted compounds. As a result, these lipophilic chemicals remain unchanged in adipose tissue with only limited amounts returning to the circulation for possible metabolism and excretion. Paradoxically, aldrin and heptachlor metabolism results in an increased rather than reduced body load. This is opposite of the pattern seen for most other pesticide classes. 

Another approach to avoiding such metabolic degradation while retaining a smaller and more polar type of R group utilizes an auxiliary compound to separately inhibit the Penicillinase, much as we saw for the case of the earlier levodopa example. For the PENs, the auxiliary compound is clavulanic acid, shovm as 66. When the beta-lactam moiety in 66 is being attacked by the Penicillinases, its unique hydroxymethylene-alkenyl system serves to further alkylate this enzyme in an irreversible manner at some other nucleophile. Hence, the enzyme cannot regenerate itself for a new attack of a beta-lactam system of any type. Thus, coadministration of 66 with a broad- or extended-spectrum PEN derivative is ultimately able to overcome the SAR paradox that is otherwise difficult to achieve within just a single molecule. 

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