Thiomers: Inhibition of cytochrome P450 activity

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• 作者：Javed Iqbal^a ; Duangkamon Sakloetsakun^b ; Andreas Bernkop-Schn&#xfc ; rch^a ; ^{andreas.bernkop@uibk.ac.at" rel="nofollow}
• 关键词：Thiomers ; Cytochrome P450 ; CYP3A4 ; CYP2A6 ; Inhibition ; Fluorescent probe assays
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2011
• 出版时间：August 2011
• 年：2011
• 卷：78
• 期：3
• 页码：361-365
• 全文大小：231 K
• ISSN：S093964111100083X

文摘

The aim of the present study was to investigate the potential of different thiolated polymers (thiomers) on the catalytic activity of CYP450s on one hand and to explore new inhibitors for CYP activity on the other hand. Several thiolated polymers including poly(acrylic acid)–cysteine (PAA–cysteine), chitosan–thioglycolic acid (chitosan–TGA), and thiolated PEG-g-PEI copolymer along with brij® 35, myrj® 52 and the well-established CYPP450 inhibitor verapamil were screened for their CYP3A4 and CYP2A6 inhibitory activity, and their IC₅₀ values were determined. Both enzyme inhibition assays were performed in 96-well microtiter plates. 7-Benzyloxy-4-(trifluoromethyl)-coumarin (BFC) and 7-hydroxycoumarin (7-HC) were used as fluorescent substrates in order to determine CYP3A4 and CYP2A6 catalytic activity, respectively. All investigated compounds inhibited CYP3A4 as well as CYP2A6 activity. All tested (thiolated) polymers were found to be more potent inhibitors of CYP3A4 than of CYP2A6 catalytic activity. Apart from verapamil that is a known CYP3A4 inhibitor, brij® 35 and myrj® 52 were explored as potent inhibitors of CYP3A4 and CYP2A6 catalytic activity. Among the tested polymers, the rank order for CYP3A4 inhibition was PAA–cysteine (100 kDa) > brij® 35 > thiolated PEG-g-PEI copolymer (16 kDa) > myrj® 52 > PAA (100 kDa) > PAA–cysteine (450 kDa) > verapamil > PAA (450 kDa) > chitosan–TGA (150 kDa) > chitosan (150 kDa). On the other hand, the rank order of CYP2A6 inhibition was brij® 35 > PAA–cysteine (100 kDa) > chitosan–TGA (150 kDa) > PAA (100 kDa) > thiolated PEG-g-PEI copolymer (16 kDa) > PAA–cysteine (450 kDa) > chitosan (150 kDa) > verapamil > PAA (450 kDa) > myrj® 52. Thus, this study suggests that (thiolated) polymers display a promising potential to inhibit cytochrome P450s activity and might turn out to be potentially valuable tools for improving the oral bioavailability of actively secreted compounds by avoiding intestinal metabolism.