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Tacrolimus Dosing in Adult Lung Transplant Patients Is Related to Cytochrome P4503A5 Gene Polymorphism

From the School of Pharmacy, University of Southern California, Los Angeles (Dr. Zheng, Dr. Burckart); School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr. Zeevi, Dr. McCurry, Dr. Griffith, Dr. Webber, Ms. Ristich, Dr. Dauber, Dr. Iacono, Mr. Grgurich, Ms. Zaldonis, Mr. McDade); and Department of Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee (Dr. Schuetz, Dr. Lamba, Dr. Zhang).

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.

Key Words: P-glycoprotein • MDR1 • CYP3A5 • polymorphism • transplantation • tacrolimus dosing

Address for reprints: Gilbert J. Burckart, PharmD, University of Southern California, 1985 Zonal Avenue, PSC-100, Los Angeles, CA 90033.

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