Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was to evaluate whether genetic polymorphisms of CYP3A5 (A6986G, CYP3A5*3), ABCB1 (C1236T, G2677T/A, C3435T) and NR1I2 (A7635G) significantly impact the pharmacokinetics of prednisolone in renal transplant recipients. Ninety-five recipients were given repeated doses of triple therapy immunosuppression consisting of prednisolone, tacrolimus and mycophenolate mofetil. Twenty-eight days after renal transplantation, plasma prednisolone concentrations were measured by high-performance liquid chromatography. Comparisons of the CYP3A5 and ABCB1 genotypes revealed no significant differences in the prednisolone pharmacokinetics. The mean prednisolone C(max) for recipients (n=14) having both the ABCB1 3435CC genotype and the CYP3A5*3/*3 genotype was significantly higher than those (n=11) having both ABCB1 3435TT and CYP3A5*3/*3 genotypes (180ng/mL versus 129ng/mL, P=0.0392). The plasma concentrations of prednisolone in recipients having both ABCB1 3435CC and CYP3A5*3/*3 genotypes tended to be higher than those having both ABCB1 3435TT and CYP3A5*3/*3 genotypes. The mean AUC(0-24) and C(max) values for prednisolone in recipients having the NR1I2 7635G allele (AG: n=45, GG: n=32) were significantly lower than in patients having the 7635AA allele (n=18) (7635GG versus 7635AA, P=0.0308 for AUC(0-24), P=0.0382 for C(max) of prednisolone). In conclusion, NR1I2 (A7635G) rather than CYP3A5 or ABCB1 allelic variants affected patient variability of plasma prednisolone concentration. Recipients carrying the NR1I2 7635G allele seemed to possess higher metabolic activity for prednisolone in the intestine, greatly reducing its maximal plasma concentration.
Steroids 2008 Oct
PMID:Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients. 1850 61

Tacrolimus is metabolized by CYP3A4 and CYP3A5 enzymes. Patients expressing CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration. CYP3A5 expressers can be considered fast metabolizers. The trough concentration/dose (C0/D) ratio of tacrolimus has recently been proposed as a prognostic marker for poor outcome after kidney transplantation. Patients with a low C0/D ratio (also referred to as fast metabolizers) seem to have more tacrolimus-related nephrotoxicity, more BK-viremia, and a lower graft survival. At first sight, the expression of CYP3A5 and a low C0/D ratio seem to be overlapping factors, both pointing towards patients in whom a higher tacrolimus dose is needed to reach the tacrolimus target concentration. However, there are important differences, and these differences may explain why the impact of the C0/D ratio on long term outcome is stronger than for CYP3A5 genotype status. Patients with a low C0/D ratio require a high tacrolimus dose and are exposed to high tacrolimus peak concentrations. The higher peak exposure to tacrolimus (and/or its metabolites) may explain the higher incidence of nephrotoxicity, BK-viremia and graft loss. A potential confounder is the concurrent maintenance treatment of corticosteroids, as steroids are sometimes continued in patients at high immunological risk. Steroids induce the metabolism of tacrolimus via pregnane X receptor mediated increased CYP3A4 expression, resulting in lower tacrolimus C0/D ratio in high risk patients. Also non-adherence may result in lower C0/D ratio which is also associated with poor outcome. The C0/D ratio of tacrolimus does seem to identify a group of patients with increased risk of poor outcome after kidney transplantation. Our recommendation is to monitor tacrolimus peak concentrations in these patients, and if these are high then target slightly lower pre-dose concentrations. Another possibility would be to switch to a prolonged release formulation or to dose the drug more frequently, in smaller doses, to avoid high peak concentrations.
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PMID:The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients. 3284 56