Abstract
Grapefruit juice has been found to cause an increase in the oral bioavailability of many therapeutic agents. Such interactions are believed to result from the mechanism-based inhibition of CYP3A4 activity in the intestine. Furanocoumarin dimers present in the juice have been found to be extremely potent inhibitors of CYP3A4 activity. The aim of this work was to synthesize and test a series of dimers with a view to defining the relationship between structure and inhibitory activity and establish whether they might make suitable probes of CYP3A4 activity. Eleven furanocoumarin dimers were synthesized and evaluated as inhibitors of CYP3A4 using human liver microsomes, with testosterone as the marker substrate. Four of the most potent dimers were also investigated for their effects on CYP3A4 activity in the human intestine and on five additional hepatic cytochrome P450 isoforms. The dimers showed potent dose-dependent inhibition of CYP3A4 activity in both liver and intestine; IC50 values ranged from 0.021 ± 0.002 to 0.146 ± 0.041 μM (mean ± S.D. n = 3). Of the four dimers evaluated further, all showed time-dependent inhibition of CYP3A4 activity. 88Prop showed moderate inhibition of both CYP2C19 and CYP1A2 with IC50 values of 4.42 ± 0.01 and 1.98 ± 0.34 μM, 88Octa was found to inhibit CYP2C19 (IC50 = 3.16 ± 0.01 μM) and 58Prop to inhibit CYP1A2 (IC50 = 2.39 ± 0.77 μM). Minimal inhibition of CYP2D6 and CYP2C9 was observed (IC50 > 10 μM). In conclusion, all the dimers tested were extremely potent inhibitors of CYP3A4 activity. In particular, dimer 55EE was highly selective toward the enzyme, suggesting that this compound is a suitable probe for determining the contribution of CYP3A4 to drug metabolism.
Footnotes
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We thank the Biotechnology and Biological Sciences Research Council (BBSRC) for financial support.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007294.
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ABBREVIATIONS: P450, cytochrome P450; EI, electron impact; CI, chemical ionization; TLC, thin-layer chromatography; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; 88cBUT, 9,9′-[(2Z)-but-2-ene-1,4-diylbis(oxy)]bis(7H-furo[3,2-g]chromen-7-one; 88tBUT, 9,9′-[(2E)-but-2-ene-1,4-diylbis-(oxy)]bis(7H-furo[3,2-g]chromen-7-one; 88Prop, 9,9′-[propane-1,3-diylbis(oxy)]bis(7H-furo[3,2-g]chromen-7-one; 88Octa, 9,9′-[(octane-1,8-diylbis(oxy)]bis(7H-furo[3,2-g]chromen-7-one; 88EE, 9,9′-[(ethane-1,2-diylbis(oxyethane-2,1-diyloxy)]bis(7H-furo[3,2-g]chromen-7-one; 55cBut, 4,4′-[(2Z)-but-2-ene-1,4-diylbis(oxy)]bis(7H-furo[3,2-g]chromen-7-one; 55tBut, 4,4′-[(2E)-but-2-ene-1,4-diylbis(oxy)bis(7H-furo[3,2-g]chromen-7-one; 55Prop, 4,4′-[(propane 1,3-diylbis(oxy)]bis(7H-furo[3,2-g]chromen-7-one; 55Octa, 4,4′-[octane-1,8-diylbis(oxy)]bis(7H-furo[3,2-g]chromen-7-one; 55EE, 4,4′-[ethane-1,2-diylbis(oxyethane-1,2-diyloxy)]bis(7H-furo[3,2-g]chromen-7-one; 58Prop, 4-({3-[(7-oxo-7H-furo[3,2-g]chromen-9-yl)oxy]propoxy}-7H-furo[3,2-g]chromen-7-one; 58Octa, 4-({8-[(7-oxo-7H-furo[3,2-g]chromen-9-yl)oxy]octyl}oxy)-7H-furo[3,2-g]chromen-7-one.
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↵1 Current affiliations: Avecia Ltd., Huddersfield, West Yorkshire, U.K. (S.A.B.); and The University of Liverpool, Department of Chemistry, Robert Robinson Laboratories, Liverpool, U.K. (E.R., A.V.S.).
- Received September 9, 2005.
- Accepted November 15, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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