Novel furanocoumarin inhibitors of CYP3A4 and P -gp

2005 2005

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Abstract (summary)

Concomitant oral administration of grapefruit juice (GFJ) with a large number of drugs produces a clinically important interaction evidenced by significantly elevated plasma concentrations of the affected medications. This well-recognized interaction has been postulated to be caused by inhibition of the drugs' metabolism by intestinal CYP3A4. However, neither the identity of the inhibitory GFJ compounds nor their effect on intestinal drug transport by P-gp or MRP2 has been examined.

In order to further investigate the involvement of furanocoumarin compounds in producing these inhibitory effects, (1) a number of racemic analogs of the natural (R)-furanocoumarins in GFJ was chemically synthesized, (2)  in vitro assays to determine the capacity of these compounds to inhibit CYP3A4 were conducted, and (3) the ability of the compounds to inhibit cellular transport in Caco-2 cells was determined.

Initially, the racemate of the natural epoxide of bergamottin was synthesized and converted this epoxide to (±)-DHB and its 8 analogs.

Subsequently, several of these furanocoumarins inhibited CYP3A4 activity, as evidenced by inhibition of triazolam (TRZ, 250 μM) α- and 4-hydroxylase activity and by inhibition of testosterone (250 μM) 6β-hydroxylase activity, in human (HLM) and rat (RLM) liver microsomes, with and without preincubation, respectively. At 2 μM, (±)-FC7 and (±)- EB inhibited formation of rat 6β-hydroxytestosterone 78% and 73%, respectively, while DHB 2 μM inhibited only 19%. In the HLM assay, of all the furanocoumarins, FC7 afforded the lowest IC 50 values. The IC50 values for inhibition of TRZ α- and 4-hydroxylation by FC7 were 0.83 ± 0.14 and 1.35 ± 0.18 μM, respectively. After preincubation, the IC50 values for inhibition of TRZ α-hydroxylation by FC1, FC2, and FC7 were 0.50 ± 0.04, 0.49 ± 0.04 and 0.47 ± 0.04 μM, respectively.

Lastly, the Caco-2 cell assay was developed. Caco-2 cells grown to monolayer density and confluence are an established model to study P-gp transporter inhibition. The cells were pre-loaded with calcein-AM and rhodamine-123 (RDM), respectively. The retention of calcein and RDM by Caco-2 cells was measured. FC1 and FC7 significantly increased the calcein and RDM retention in Caco-2 cells.

In conclusion, the data confirm that several of the newly synthesized furanocoumarins are strong inhibitors of both CYP3A4 and cellular transporters, and provide evidence that the natural analogs present in GFJ participate in causing the well known food-drug interactions.

Indexing (details)

Organic chemistry
0491: Pharmacology
0490: Organic chemistry
0419: Pharmacology
Identifier / keyword
Health and environmental sciences; Pure sciences; CYP3A4; Furanocoumarin; P-gp
Novel furanocoumarin inhibitors of CYP3A4 and P -gp
Jen, Cheng
Number of pages
Publication year
Degree date
School code
DAI-B 66/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
0542213672, 9780542213670
LeDuc, Barbara W.; Kelley, Charles J.
Massachusetts College of Pharmacy and Health Sciences
University location
United States -- Massachusetts
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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