Zheng HongXia, Zeevi Adriana, Schuetz Erin, Lamba Jatinder, McCurry Kenneth, Griffith Bartley P, Webber Steven, Ristich Julianne, Dauber James, Iacono Aldo, Grgurich Wayne, Zaldonis Diana, McDade Kevin, Zhang Jiong, Burckart Gilbert J
School of Pharmacy, University of Southern California, 1985 Zonal Avenue, PSC-100, Los Angeles, CA 90033, USA.
J Clin Pharmacol. 2004 Feb;44(2):135-40. doi: 10.1177/0091270003262108.
Tacrolimus is a potent immunosuppressive agent used in lung transplantation and is a substrate for both P-glycoprotein (P-gp, encoded by the gene MDR1) and cytochrome (CYP) P4503A. A previous study by the authors identified a correlation between the tacrolimus blood level per dose with CYP3A5 and MDR1 gene polymorphisms in pediatric heart transplant patients. The objective of this study was to confirm the influence of these polymorphisms on tacrolimus dosing in adult lung transplant patients. Adult lung transplant patients who had been followed for at least 1 year after lung transplantation were studied. Tacrolimus blood level (ng/mL) per dose (mg/day) at 1, 3, 6, 9, and 12 months after transplantation was calculated as [L/D]. DNA was extracted from blood. MDR1 3435 CC, CT, and TT; MDR1 2677 GG, GT, and TT; and CYP3A5*1 (expressor) and *3 (nonexpressor) genotypes were determined by PCR amplification, direct sequencing, and sequence evaluation. Eighty-three patients were studied. At 1, 3, 6, 9, and 12 months after the transplant, a significant difference in [L/D] was found between the CYP3A5 expressor versus nonexpressor genotypes (mean +/- SD of 1.49 +/- 0.88 vs. 3.11 +/- 4.27, p = 0.01; 1.23 +/- 0.82 vs. 3.44 +/- 8.97, p = 0.05; 1.32 +/- 0.96 vs. 3.81 +/- 6.66, p = 0.005; 0.95 +/- 1.19 vs. 3.74 +/- 5.98, p = 0.0015; and 0.45 +/- 0.2 vs. 3.76 +/- 6.75, p = 0.0001, respectively). MDR1 G2677T and C3435T genotypes had only minimal effects on [L/D] at 1 and 3 months after transplantation. This study confirms the relationship of CYP3A5 polymorphisms to tacrolimus dosing in organ transplant patients. CYP3A5 expressor genotypes required a larger tacrolimus dose to achieve the same blood levels than the CYP3A5 nonexpressors at all time points during the first posttransplant year. This was not uniformly true for MDR1. The authors therefore conclude that tacrolimus dosing in adult lung transplant patients is associated with CYP3A5 gene polymorphisms.
他克莫司是一种用于肺移植的强效免疫抑制剂，是P-糖蛋白（P-gp，由MDR1基因编码）和细胞色素（CYP）P4503A的底物。作者之前的一项研究确定了小儿心脏移植患者每剂量他克莫司血药浓度与CYP3A5和MDR1基因多态性之间的相关性。本研究的目的是证实这些多态性对成人肺移植患者他克莫司给药的影响。对肺移植后至少随访1年的成人肺移植患者进行了研究。移植后1、3、6、9和12个月时每剂量（毫克/天）的他克莫司血药浓度（纳克/毫升）计算为[L/D]。从血液中提取DNA。通过PCR扩增、直接测序和序列评估确定MDR1 3435 CC、CT和TT；MDR1 2677 GG、GT和TT；以及CYP3A51（表达型）和3（非表达型）基因型。研究了83例患者。在移植后1、3、6、9和12个月时，CYP3A5表达型与非表达型基因型之间的[L/D]存在显著差异（平均值±标准差分别为1.49±0.88对3.11±4.27，p = 0.01；1.23±0.82对3.44±8.97，p = 0.05；1.32±0.96对3.81±6.66，p = 0.005；0.95±1.19对3.74±5.98，p = 0.0015；以及0.45±0.2对3.76±6.75，p = 0.0001）。MDR1 G2677T和C3435T基因型在移植后1和3个月时对[L/D]的影响极小。本研究证实了CYP3A5多态性与器官移植患者他克莫司给药之间的关系。在移植后的第一年，CYP3A5表达型基因型在所有时间点都需要比CYP3A5非表达型基因型更大剂量的他克莫司才能达到相同的血药浓度。MDR1并非始终如此。因此，作者得出结论，成人肺移植患者的他克莫司给药与CYP3A5基因多态性有关。
