Lipophilic conjugates

Okuno, Y., T. Seki, S. Ito, H. Kenoko, T. Watanabe, T. Yamada, and J. Miyamoto. 1986. Differential metabolism of fenvalerate and granuloma formation. II. Toxicological significance of a lipophilic conjugate from fenvalerate. Toxicol. Appl. Pharmacol. 83 157-169. 

In addition, three types of lipophilic conjugates have been found in pyrethroid metabolism studies (Fig. 4). They are cholesterol ester (fenvalerate) [15], glyceride (3-PBacid, a common metabolite of several pyrethroids) [16], and bile acid conjugates (fluvalinate) [17]. It is noteworthy that one isomer out of the four chiral isomers of fenvalerate yields a cholesterol ester conjugate from its acid moiety [15]. This chiral-specific formation of the cholesterol ester has been demonstrated to be mediated by transesterification reactions of carboxylesterase(s) in microsomes, not by any of the three known biosynthetic pathways of endogenous cholesterol esters... 

Pignatello R, et al. Effect of liposomal delivery on in vitro antitumor activity of lipophilic conjugates of methotrexate with lipoamino acids. Drug Deliv 2003 10 95. 

Lipophilic conjugate acids with low pKaS will pass back into the blood. 

With lipophilic conjugation, the xenobiotic metabolites appear to be incorporated in the lipid biosynthetic pathway similar to the normal constituents. One would expect the conjugates to have turnover times similar to that of their natural counterparts. Whether the lipophilic conjugates have any deleterious effect on the organism would depend upon the type and amount of bioactivity retained by the metabolites before and after conjugation. 

Most xenobiotic conjugation reactions in plants and animals lead Initially to the fornation of polar products such as glycoside or glutathione conjugates, but several reports indicate that plants (144-148) and animals (249) may also form lipophilic conjugates. 

Recently, a very different class of lipophilic conjugates of picloram and 2,4-D were isolated from radish and mustard plants... 

This presentation will not be a review, but will attempt to place within a frame of the presently used techniques and methods my very personal experiences and views. This discussion will be limited to the "classical" pqlar conjugates. Very different methodology is required to purify the non polar "lipophilic" conjugates. Furthermore, only methods that result in the Isolation of intact conjugates in amounts adequate for multiple-method structural Identification studies will be discussed (i.e. combined methods such as GC-MS and HPLC-MS and derivatization techniques will not be covered). 

This review emphasizes recent examples of novel lipophilic conjugates. Previously reviewed nonpolar conjugates (1-3) are considered only briefly and although certain relatively simple conjugations (e.g. methylation, formylatlon, and acetylation) also... 

The esters utilized oleic, palmitic, linoleic, stearic, palmitoleic, myristic, and laurlc acids, but collectively these lipophilic conjugates represented <0.1% of the applied dose. The hydroxyethyl groups of dlpyrldamol (a coronary vasodilator) and mopldamol (a cytostatic agent) are esterified with oleic and palmitic acids (35). These lipophilic derivatives of both drugs are excreted In feces (about 4X of the applied dose for rats and humans). 

The fate of plant xenobiotic conjugates I.e. glycosides, malonates, N-acyl-amlno acids, alkyl/aryl glutathiones and derivatives, lipophilic conjugates and polymer conjugates (bound residues). In animals Is reviewed. Some classes are reasonably well-studied but no Information Is available for others. 

Some carboxylic acids that can form highly lipophilic conjugates (Fig. 27, reactions 3 and... 

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