Minimal contribution of the hepatic uptake transporter OATP1B1 to the inter-individual variability in SN-38 pharmacokinetics in cancer patients without severe renal failure
Minimal contribution of the hepatic uptake transporter OATP1B1 to the inter-individual variability in SN-38 pharmacokinetics in cancer patients without severe renal failure
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DOI：
10.1007/s00280-021-04314-1
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发表时间：
2021-06-11
影响因子：
3
通讯作者：
Fujita, Ken-ichi
中科院分区：
文献类型：
--
作者：
Tsuboya, Ayako;Kubota, Yutaro;Fujita, Ken-ichi
目的SN-38是伊立替康的代谢产物，经有机阴离子转运多肽（OATP）1B 1摄取进入肝细胞。功能性OATP 1B 1 521 T>C对SN-38药代动力学的影响仍存在争议。在此，我们通过评估接受伊立替康治疗的癌症患者中的OATP 1B 1 521 T>C和内源性OATP 1B 1底物粪卟啉（CP）-I和III的血浆水平，前瞻性地检查了OATP 1B 1功能对SN-38的血浆总或未结合浓度-时间曲线下面积（tAUC或uAUC）的影响。方法我们招募了接受含伊立替康方案治疗且未发生严重肾衰竭的癌症患者。通过高效液相色谱法测定血浆中SN-38的总浓度和未结合浓度。计算AUC值，并标准化为实际伊立替康剂量（AUC/剂量）。通过直接测序分析OATP 1B 1 521 T>C。通过液相色谱串联质谱法测定伊立替康治疗前（基线）血浆中内源性底物的浓度。结果22例患者的肾小球滤过率中位数为74.8 mL/min（范围32.6-99.6）。tAUC/剂量和uAUC/剂量均与中性粒细胞减少分级相关;然而，它们与OATP 1B 1 521 T>C或基线CP-I和III水平无关。值得注意的是，OATP 1B 1 521 C患者的这些基线浓度显著更高，支持OATP 1B 1的功能变化。结论在无重度肾衰竭的患者中，OATP 1B 1活性对SN-38全身暴露量的患者间变异性的贡献可能很小。
Purpose SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan. Methods We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry. Results Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1. Conclusion The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.