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.

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.

Made available in DSpace on 2015-04-01T14:16:02Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 578629 bytes, checksum: 0e1eef478991e7f411dddd815ac56a75 (MD5) Previous issue date: 2013-08-09 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Furocoumarins (FCs) are an important class of photoactive compounds which may potentially bind to DNA forming intermolecular complexes, and once excited by UVA light (~ 365 nm) they re able to form photoadducts, which may result in mutagenicity and lethality. However, when the 8-methoxypsoralen (8-MOP) is added to the post-irradiation plating medium increases the sensitization probably by inhibiting repairs in damaged DNA. The FCs also have a protective effect against UVC (~254 nm) attributed to the inhibition of pyrimidine dimers. FCs associated with UVB light (312 nm), remain few known. The aim of the present study was to investigate the lethal effect of UVB light alone, and combined with solutions of 8-MOP, 4,5',8-trimethylpsoralen (TMP) and 3-carbetoxypsoralen (3-CPs) at different concentrations on Staphylococcus aureus growth. We also evaluated the effect of these FCs in the plating medium. Treatment with 8-MOP-UVB and TMP-UVB were more effective in inducing lethality than the UVB treatment alone. Increasing the solution concentration of 8-MOP resulted in a higher mortality while the increase in the concentration of the TMP led to a reduction in the lethality. For other hand, 3-CPs displayed a photoprotective effect against UVB damage in all concentrations tested. The results of FCs in the plating medium showed that the 8-MOP induzed a higher lethal effect and also increased mortality from bacterial strain treated by FC-UVB. The different behaviors shown by FCs may be related with differences in the sequence specificity of binding and photoreaction, inhibition of pyrimidine dimers formation by intercalated molecules and efficacy of repair systems. These results emphasize the need for further studies to elucidate the participation of FCs as photosensitizing and photoprotective agents in biological systems, when combined with UVB. / As furocumarinas (FCs) são uma importante classe de compostos fotoativos que potencialmente podem se ligar ao DNA formando complexos intermoleculares, e uma vez excitados por luz UVA (~365 nm) são capazes de formar fotoadições, que podem resultar em mutagênese e letalidade. Porém, quando a 8-metoxipsoraleína (8-MOP) está adicionada ao meio de plaqueamento pós-irradiação aumenta a sensibilidade provavelmente por inibir reparo de lesões no DNA. As FCs também possuem efeito protetor contra UVC (~254 nm) atribuído à inibição da formação de dímeros de pirimidina. As FCs associadas à UVB (312 nm) permanecem pouco conhecidas. O objetivo do presente estudo foi investigar o efeito da luz UVB, e combinada com soluções de 8-MOP, 4,5 ,8-trimetilpsoraleína (TMP) e 3-carbetoxipsoraleína (3-CPs) em diferentes concentrações, sobre o crescimento de Staphylococcus aureus. Avaliamos também o efeito destas FCs em meio de plaqueamento. O tratamento com 8-MOP-UVB e TMP-UVB foram mais eficazes em induzir letalidade do que o tratamento apenas com UVB. O aumento da concentração de 8-MOP resultou em mortalidade mais elevada enquanto que o aumento na concentração de TMP levou a redução na mortalidade. Por outro lado, 3-CPs exibiu efeito fotoprotetor contra danos causados por UVB em todas as concentrações testadas. Os resultados com FCs no meio de plaqueamento mostraram que a 8-MOP induziu o maior efeito letal e também aumentou a mortalidade da cepa bacteriana tratada por FC-UVB. Os diferentes efeitos apresentados pelas FCs podem estar relacionados com diferenças na especificidade por seqüência de ligação e fotorreação, a inibição da formação de dímeros de pirimidina por moléculas intercaladas e eficácia de sistemas de reparo. Esses resultados reforçam a necessidade de mais estudos para elucidar a participação das FCs como agentes fotossensibilizantes e fotoprotetores em sistemas biológicos, quando combinadas com UVB.