| Summary: | Cyclosporine forms the cornerstone of therapy to prevent rejection after organ transplantation.
However, the clinical use of the drug is compromised by a narrow therapeutic window and a
wide inter- and intra-individual variation in metabolism. Cyclosporine is metabolised by the
CYP3A4 isoenzymes in both the liver and intestine, while it has been reported that the
metabolism of the drug can be inhibited by certain furocoumarin derivatives in grapefruit juice.
Methoxsalen (8-methoxypsoralen) is a furocoumarin and a potent inhibitor of the cytochrome
P450 system in both the liver and intestine. The study was conducted to investigate the
possibility whether methoxsalen may inhibit the metabolism of cyclosporine and thereby
increase the bioavailability of the drug. The interaction is of clinical relevance since both drugs
are used in the treatment of psoriases.
The study, conducted in 12 healthy male volunteers, was a three-way comparative bioavailability
study with a wash out period of one week between treatments. The patients received 40 mg
methoxsalen, 200 mg cyclosporine or a combination of the two on three separate occasions.
Blood samples of 10 ml were collected by venupuncture at the following times: 0, 0.5, 1, 1.5, 2,
2.5, 3.4, 5,6, 8, 12 and 24 hours after drug administration. Methoxsalen was analysed by a high
pressure liquid chromatograph method (HPLC) with UV detection (LOQ = 10 ng/ml), while
cyclosporine was analysed using a fluorescence polarisation immunoassay (FPIA) technique.
There was a statistical significant difference in AUCo-00 and Cmax ' for cyclosporine when
methoxsalen was added to the drug regimen. When the methoxsalen levels were compared with
those in the presence of cyclosporine, the levels were lower, although the difference was not
statistical significant. We conclude that methoxsalen increase the levels of cyclosporine by
inhibiting the P450 system enzymes in the liver and intestine. However, the absorption of
methoxsalen is highly variable in the same individual which needs to be considered before this
interaction can be regarded as being of any clinical relevance. === Thesis (M.Sc.(Pharmacology))--North-West University, Potchefstroom Campus, 2004.
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