Abstract
Tacrolimus is a macrolide immunosuppressant used to prevent allograft rejection in organ transplantation. CYP3A4, CYP3A5, and P‐glycoprotein (MDR1) may play significant roles in drug disposition of xenobiotics including tacrolimus. Single nucleotide polymorphisms (SNPs) in CYP3A4 (A‐290G), CYP3A5 (A22893G), and MDR1 (C3435T) may result in altered in vivo catalytic activity. This study explored the pharmacogenomic impact of CYP3A4, CYP3A5, and MDR1 on tacrolimus dosing and clinical outcomes in liver transplant recipients.
In 45 patients, phenotypic data were collected for the first 10 days post‐transplant and at Month 4. Genomic DNA was isolated from human liver tissue with genotypic determination done via PCR‐based detection methods. Unpaired T‐tests compared two genotype groups with P<0.05 considered significant.
Significantly, CYP3A4 AA genotype had higher mean tacrolimus trough concentrations than AG/GG (11.8±2.7 vs 9.7±2.9 mcg/dL, p=0.027), and individuals with CYP3A5*3/*3 required higher tacrolimus doses than those with a CYP3A5*1 allele (0.054±0.02 vs 0.040±0.02 mg/kg/d, p=0.040). Renal clearance significantly declined from transplant to Month 4 in all groups (p<0.0001), but no genotype interactions were identified.
Thus, genetic variants of CYP3A4 and CYP3A5 may be useful predictors of tacrolimus requirements and outcomes in liver transplant patients and may contribute to the construction of clinically relevant pharmacogenomic models in transplantation.
Clinical Pharmacology & Therapeutics (2004) 75, P39–P39; doi: 10.1016/j.clpt.2003.11.149