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The influences of human MDR1 gene polymorphisms on pharmacokinetics of tacrolimus in renal transplant recipients
Author(s) -
Uchida S.,
Takai N.,
Hashimoto H.,
Furuse H.,
Kageyama S.,
Ushiyama T.,
Suzuki K.,
Ozono S.,
Yamada H.,
Watanabe H.,
Ohashi K.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.062
Subject(s) - tacrolimus , pharmacokinetics , genotype , pharmacology , dosing , medicine , immunosuppressive drug , transplantation , biology , gene , genetics
Objective Tacrolimus is a largely used immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Recently, it has been reported that polymorphisms in P‐glycoprotein (the product of the multiple drug resistant gene MDR1) altered pharmacokinetic profiles of its substrate drugs. The aim of this study was to clarify the influence of MDR1 gene polymorphisms on pharmacokinetics of tacrolimus in renal transplant recipients. Methods Blood tacrolimus concentrations after intravenous and oral administration were measured in 31 Japanese renal transplant recipients. The blood concentration and polymorphisms in exon 21 (G2677A/T) and exon 26 (C3435T) of MDR1 genotype were determined by a microparticle enzyme immunoassay and polymerase chain reaction‐restriction fragment length polymorphism, respectively. Results There were 16 homozygous C/C (51.6%), 11 heterozygous C/T (35.5%) and 4 homozygous T/T (12.9%) genotypes in the recipients. Dose‐adjusted trough concentrations of tacrolimus in C/C, C/T and T/T genotypes were 93.4±44.9, 63.4±49.0 and 115±46.5 ng/ml/mg/kg (mean±SD), respectively, and the difference of each group was not significant. The ratio of AUC(0–6) for oral dosing to AUC(0–6) for intravenous dosing in T/T genotype was significantly higher than in C/C and C/T genotypes. Conclusion These findings suggested that the MDR1 polymorphism altered the pharmacokinetics of tacrolimus. Clinical Pharmacology & Therapeutics (2004) 75 , P17–P17; doi: 10.1016/j.clpt.2003.11.062