肾移植后静脉用尼卡地平治疗 CYP3A5 无表达者的他克莫司毒性风险。
Risk of tacrolimus toxicity in CYP3A5 nonexpressors treated with intravenous nicardipine after kidney transplantation.
机构信息
Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
出版信息
Transplantation. 2012 Apr 27;93(8):806-12. doi: 10.1097/TP.0b013e318247a6c7.
BACKGROUND
Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5.
METHODS
We compared maximum 12-hr tacrolimus trough levels (MaxC0) and dose-adjusted MaxC0 in 12 cases treated with CIVN immediately after kidney transplantation with 26 controls (no CIVN). CYP3A5 genotype was determined for all cases.
RESULTS
Eight cases not expressing CYP3A5 (CYP3A5*3/3) had higher median MaxC0 (24.3 ng/mL) than four cases expressing CYP3A5 (CYP3A51/1; 13.9 ng/mL, P=0.028) and controls (14.6 ng/mL, P=0.003). Compared with the other two groups combined, CYP3A53/3 cases had higher median dose-adjusted MaxC0 (330 vs. 175, P=0.012), less time to MaxC0 (42 vs. 72 hr, P<0.001), and more scheduled tacrolimus doses held per patient (1.75 vs. 0.4, P=0.007). Six of eight (75%) CYP3A5*3/*3 cases had potentially toxic MaxC0 (>20 ng/mL) compared with none of four CYP3A51/1 cases and 3 of 26 (11.5%) controls (P<0.001, CYP3A53/*3 cases vs. all others).
CONCLUSION
CYP3A5 nonexpressors simultaneously treated with tacrolimus and CIVN may be at increased risk for tacrolimus toxicity.
背景
他克莫司常用于免疫抑制，但会导致急性和慢性肾损伤。尼卡地平持续静脉输注（CIVN）用于移植后高血压，通过细胞色素 P450（CYP）3A4 抑制他克莫司代谢，在 CYP3A5 代谢替代途径缺失的患者中，可能导致他克莫司暴露过度。
方法
我们比较了 12 例肾移植后立即接受 CIVN 治疗的患者（12 小时内的最大他克莫司谷值（MaxC0）和剂量调整后的最大他克莫司谷值（MaxC0））与 26 例对照（未使用 CIVN）。所有患者均检测了 CYP3A5 基因型。
结果
8 例不表达 CYP3A5（CYP3A5*3/3）的患者的中位 MaxC0（24.3ng/ml）高于 4 例表达 CYP3A5（CYP3A51/1；13.9ng/ml，P=0.028）和对照组（14.6ng/ml，P=0.003）。与其他两组相比，CYP3A53/3 患者的中位剂量调整后 MaxC0 更高（330 与 175，P=0.012），达到 MaxC0 的时间更短（42 与 72 小时，P<0.001），每位患者需要维持的他克莫司剂量更高（1.75 与 0.4，P=0.007）。8 例 CYP3A5*3/*3 患者中有 6 例（75%）的 MaxC0 可能有毒性（>20ng/ml），而 4 例 CYP3A51/1 患者中无 1 例，26 例对照组中仅有 3 例（11.5%）（P<0.001，CYP3A53/*3 患者与其他所有患者相比）。
结论
同时接受他克莫司和 CIVN 治疗的 CYP3A5 非表达者可能有更高的他克莫司毒性风险。
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