Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome p450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP) and another monohydroxylated paclitaxel. In human liver microsomes, 6alpha-hydroxypaclitaxel (6alpha-OHP), formed by CYP2C8, was the main metabolite, while C3'-OHP, C2-OHP and another product different from di-OHP were minor metabolites, formed by CYP3A4. In individual human livers 6alpha-OHP was formed at 1.8-fold to 13-fold higher rates than C3'-OHP. Kinetic parameters (K(m) and V(max)) of production of various metabolites in rat and human liver microsomes revealed differences between species as well as human individual differences. Nine phenolic antioxidants ((+)-catechin, (-)-epicatechin, fisetin, gallic acid, morin, myricetin, naringenin, quercetin and resveratrol) were tested for inhibition of paclitaxel metabolism. In rat microsomes, resveratrol was more inhibitory than fisetin; the other phenolic antioxidants were without effect. In human microsomes, the inhibiting potency decreased in the order fisetin >quercetin >morin >resveratrol, while the other phenolic antioxidants were not inhibitory; the formation of 6alpha-OHP (CYP2C8) was generally more inhibited than that of C3'-OHP. The inhibition was mostly mixed-type. The results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy.

• MeSH
• antagonismus léků MeSH
• antioxidancia farmakologie   MeSH
• aromatické hydroxylasy antagonisté a inhibitory   metabolismus   MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2C8 MeSH
• dospělí MeSH
• druhová specificita MeSH
• fenoly farmakologie   MeSH
• fytogenní protinádorové látky antagonisté a inhibitory   chemie   metabolismus   MeSH
• jaterní mikrozomy enzymologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mladiství MeSH
• N-demethylasy antagonisté a inhibitory   metabolismus   MeSH
• paclitaxel antagonisté a inhibitory   chemie   metabolismus   MeSH
• potkani Wistar MeSH
• techniky in vitro MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antioxidancia MeSH
• aromatické hydroxylasy MeSH
• CYP2C8 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2C8 MeSH
• fenoly MeSH
• fytogenní protinádorové látky MeSH
• N-demethylasy MeSH
• paclitaxel MeSH