The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation.

BACKGROUND: tacrolimus and everolimus are immunosuppressive drugs metabolized by enzymes of the CYP3A subfamily. A common variant of the CYP3A5 gene, CYP3A5*3, results in strongly decreased CYP3A5 activity and has been shown to influence Tacrolimus blood concentrations, but its role for the pharmacogenetics of Everolimus remains unclear. Aim of the study was to examine the role of CYP3A5*3 variant in tacrolimus and everolimus dose and drug levels after heart transplantation. METHODS: The present study comprised 15 patients with Tacrolimus and 30 patients with Everolimus-based maintenance therapy after heart transplantation. CYP3A5 genotypes were determined and correlated with clinical data. RESULTS: In the Tacrolimus group, 13 subjects were CYP3A5 non-expressors (*3/*3 genotype) and two were heterozygous expressors (*1/*3 genotype). Average Tacrolimus dose was significantly higher in subjects expressing CYP3A5 compared to non-expressors. Tacrolimus levels were not significantly different at any point of time. In the Everolimus group, 27 subjects were CYP3A5 non-expressors (*3/*3 genotype) and three were heterozygous expressors (*1/*3). Neither Everolimus dose nor levels were significantly different between CYP3A5 expressors and non-expressors at any point of time. DISCUSSION: We conclude that in adult patients after heart transplantation, CYP3A5 genotypes have a strong influence on Tacrolimus, but not Everolimus dose requirement.

Bioactive 1,4-dihydroisonicotinic acid derivatives prevent oxidative damage of liver cells.

1,4-Dihydroisonicotinic acid derivatives (1,4-DHINA) are compounds closely related to derivatives of 1,4-dihydropyridine, a well-known calcium channel antagonists. 1,4-DHINA we used were derived from a well-known antioxidant Diludin. Although some compounds have neuromodulatory or antimutagenic properties, their activity mechanisms are not well known. This study was performed to obtain data on antioxidant and bioprotective activities of: 2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydroisonicotinic acid (Ia); sodium 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)glutamate (Ib) and sodium 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)ethane-sulphate (Ic). 1,4-DHINA's activities were studied in comparison to Trolox by: N,N-Diphenyl-N'-picrylhydrazyl (DPPH*), deoxyribose degradation, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) radical scavenging and antioxidative capacity assays; copper-induced lipid peroxidation of cultured rat liver cells (malondialdehyde determination by high performance liquid chromatography and 4-hydroxynonenal-protein conjugates by dot-blot); (3)H-thymidine incorporation and trypan blue assay for liver cells growth and viability. In all assays used Ia was the most potent antioxidant. Ia was also a potent antioxidant at non-toxic concentrations for liver cell cultures. It completely abolished, while Ic only slightly decreased copper-induced lipid peroxidation of liver cells. Thus, antioxidant capacities are important activity principle of Ia, which was even superior to Trolox in the cell cultures used, while activity principles of Ic and Ib remain yet to be determined.