BACKGROUND
Recent studies have identified new candidate polymorphisms in the genes related to CYP3A activity or calcineurin inhibitor dose requirements in kidney transplant recipients. These genes and polymorphisms are CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (rs35599367-C>T; *22); POR [P450 (cytochrome) oxidoreductase] (rs1057868-C>T; *28); and PPARA (peroxisome proliferator-activated receptor alpha) (rs4253728-G>A). We investigated the impact of these polymorphisms on sirolimus (SRL) in vitro hepatic metabolism, SRL trough concentrations (C0), and SRL adverse events in kidney transplant recipients.
METHODS
The clinical study included 113 stable kidney transplant patients switched from a calcineurin inhibitor to SRL (SRL C0 measured at 1, 3, and 6 months thereafter). We investigated SRL metabolism in vitro using human liver microsomes derived from individual donors (n = 31). Microsomes and patients were genotyped by use of Taqman® allelic discrimination assays. The effects of polymorphisms and covariates were studied using multilinear regression imbedded in linear mixed-effect models or logistic regressions.
RESULTS
In vitro, the CYP3A4*22 allele resulted in approximately 20% lower metabolic rates of SRL (P = 0.0411). No significant association was found between CYP3A4, CYP3A5, or PPARA genotypes and SRL dose, C0, or C0/dose in kidney transplant patients. POR*28 was associated with a minor but significant decrease in SRL log-transformed C0 [CT/TT vs CC, β = −0.15 (0.05); P = 0.0197] but this did not have any impact on the dose administered, which limited the relevance of the finding. After adjustment for nongenetic covariates and correction for false discovery finding, none of the single-nucleotide polymorphisms tested showed significant association with SRL adverse events.
CONCLUSIONS
These recently described polymorphisms do not seem to substantially influence the pharmacokinetics of SRL or the occurrence of SRL adverse events in kidney transplant recipients.
We report the synthesis, the structure
determination, and the structure analysis of La34Mo8O75, which comprises 68 mol % La2O3 in the binary system La2O3–MoO3, in place of the previously reported compound La4MoO9, 66.7 mol % La2O3. This latter
compound, which was reported in the literature without any structural
information, is presented in this Article as part of the exploration
of the La2O3–Nb2O5–MoO3 ternary phase diagram. Several diffraction
techniques were used for the structural resolution of this compound
such as powder X-ray and neutron diffraction as well as transmission
electron microscopy in diffraction mode. La34Mo8O75 crystallizes in the monoclinic space group C2/m with the cell parameters: a = 17.070 Å, b = 12.204 Å, c = 9.742 Å, β = 109.58°. The structure,
related to fluorite, can be described as an anion-deficient fluorite
with the global formula La34Mo8O75□9. The oxygen conduction of the compound was also
investigated by means of complex impedance spectroscopy.
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