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<p>Tacrolimus (TAC) exhibits substantial interindividual pharmacokinetic variability, complicating early dose optimization after kidney transplantation. This study evaluated the effects of <i>CYP3A5</i> rs776746 (6986A &gt; G), <i>CYP3A4</i> rs4646437 (G &gt; A), and <i>ABCB1</i> rs1045642 (3435C &gt; T) genetic variations on TAC metabolism during the first post-transplant month. In 120 kidney transplant recipients, TAC exposure was assessed using dose-normalized trough concentrations (C<sub>0</sub>/D), and patients with a low C<sub>0</sub>/D ratio (&lt;1.05 ng/mL per mg/day) were classified as fast metabolizers, whereas those with a high C<sub>0</sub>/D ratio (≥1.05 ng/mL per mg/day) were classified as slow metabolizers. Fast metabolizers (48.3%) had lower TAC trough levels, required higher doses, and showed reduced C<sub>0</sub>/D ratios compared with slow metabolizers (0.95 ± 0.12 vs 2.39 ± 0.53 ng/mL per mg/day; <i>p</i> &lt; 0.001). <i>CYP3A5</i> rs776746 was the primary determinant, with each A allele strongly associated with fast metabolism (adjusted OR 44.11, 95% CI 11.70–166.36; <i>p</i> &lt; 0.001). <i>CYP3A4</i> rs4646437 provided additional stratification, whereas <i>ABCB1</i> rs1045642 showed modest effects. Combined <i>CYP3A5/CYP3A4</i> risk genotypes identified fast metabolizers in 88.2% of cases. These findings support genotype-informed TAC dosing to improve early post-transplant exposure.</p>

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Effects of CYP3A4, CYP3A5, and ABCB1 genetic variants on tacrolimus metabolism during the early period after kidney transplantation

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Nahathai Dukaew,
  • Kajohnsak Noppakun,
  • Mingkwan Na Takuathung,
  • Nattharinee Kongta,
  • Ratchanon Inpan,
  • Naruemon Suyayai,
  • Nut Koonrungsesomboon

摘要

Tacrolimus (TAC) exhibits substantial interindividual pharmacokinetic variability, complicating early dose optimization after kidney transplantation. This study evaluated the effects of CYP3A5 rs776746 (6986A > G), CYP3A4 rs4646437 (G > A), and ABCB1 rs1045642 (3435C > T) genetic variations on TAC metabolism during the first post-transplant month. In 120 kidney transplant recipients, TAC exposure was assessed using dose-normalized trough concentrations (C0/D), and patients with a low C0/D ratio (<1.05 ng/mL per mg/day) were classified as fast metabolizers, whereas those with a high C0/D ratio (≥1.05 ng/mL per mg/day) were classified as slow metabolizers. Fast metabolizers (48.3%) had lower TAC trough levels, required higher doses, and showed reduced C0/D ratios compared with slow metabolizers (0.95 ± 0.12 vs 2.39 ± 0.53 ng/mL per mg/day; p < 0.001). CYP3A5 rs776746 was the primary determinant, with each A allele strongly associated with fast metabolism (adjusted OR 44.11, 95% CI 11.70–166.36; p < 0.001). CYP3A4 rs4646437 provided additional stratification, whereas ABCB1 rs1045642 showed modest effects. Combined CYP3A5/CYP3A4 risk genotypes identified fast metabolizers in 88.2% of cases. These findings support genotype-informed TAC dosing to improve early post-transplant exposure.