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dc.contributor.advisorRheeders, M.
dc.contributor.authorBouwer, Máralien
dc.date.accessioned2009-02-04T09:02:01Z
dc.date.available2009-02-04T09:02:01Z
dc.date.issued2003
dc.identifier.urihttp://hdl.handle.net/10394/331
dc.descriptionThesis (M.Sc.(Pharmacology))--North-West University, Potchefstroom Campus, 2004.
dc.description.abstractCyclosporine 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.
dc.publisherNorth-West University
dc.subjectCyclosporineen
dc.subjectMethoxsalenen
dc.subjectFurocoumarinen
dc.subjectGrapefruit juiceen
dc.subjectCytochrome P450en
dc.subjectIntestinal metabolismen
dc.subjectHPLCen
dc.titleThe pharmacokinetic interaction between cyclosporine and methoxsalenen
dc.typeThesisen
dc.description.thesistypeMasters


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