Paclitaxel 6a-hydroxylation

Figure 3 Effect of protein concentration on the inhibition of CYP2C8 (paclitaxel 6a-hydroxylation) by montelukast in human liver microsomes. The inhibitory effect of montelukast (CYP2C8 inhibitor) on the conversion of paclitaxel to 6a-hydroxypaclitaxel declined almost 20-fold when the microsomal protein concentration increased 20-fold due to nonspecific protein binding.

Metabolism study of new fluorine-containing taxoids. Enzyme inhibition studies have shown that the cytochrome P-450 (CYP) family of enzymes is playing a key role in the biotransformation of paclitaxel and docetaxel. It has been found that the CYP 2C enzyme subfamily is responsible for the 6a-hydroxylation of paclitaxel, while the CYP 3 A subfamily plays a key role in the hydroxylation of the Boc group of docetaxel as well as that of the 3 -phenyl and 2-benzoyl groups of paclitaxel (Figure 1) (11,25)... 

Taxol (Paclitaxel) 137, a natural product derived from the bark of the Pacific yew, Taxus brevifolia [213-215], and the hemisynthetic analogue Docetaxel (Taxotere) 138, two recent and promising antitumour agents, have been the matter of extensive in vivo and in vitro animal metabolic studies. The major metabolites of taxol excreted in rat bile [216] were identified as a C-4 hydroxylated derivative on the phenyl group of the acyl side chain at C-13 (139), another aromatic hydroxylation product at the mefa-position on the benzoate group at C-2 (140) and a C-13 deacylated metabolite (baccatin III, 142) the structure of six minor metabolites could not be determined. The major human liver microsomal metabolite, apparently different from those formed in rat [217], has been identified as the 6a-hydroxytaxol (141) [218, 219]. A very similar metabolic pattern was... 

A paclitaxel analog with a C4—C6 bridge, built on the connection of a carboxyl group of 4-glutarate and the hydroxyl group of 6a-hydroxyacetate, was found almost inactive. This observation was in accordance with the hypothesis that the Southern Hemisphere of paclitaxel binds to the tubulin receptor. 

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