Franke R M, Baker S D, Mathijssen R H, Schuetz E G, Sparreboom A
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clin Pharmacol Ther. 2008 Dec;84(6):704-9. doi: 10.1038/clpt.2008.94. Epub 2008 May 28.
We hypothesized that the assessment of baseline CYP3A4 activity is influenced by probe-specific differences in hepatocellular uptake mechanisms. There was no significant correlation between the erythromycin breath test (ERMBT) parameters and midazolam clearance in 30 cancer patients (R(2) < 0.01), regardless of their CYP3A5 genotype status. In cellular models overexpressing 10 different solute carriers, erythromycin uptake was significantly increased by OATP1A2 (P < 0.005) and OATP1B3 (P < 0.01). Midazolam was not a substrate for any of the tested transporters. In a separate cohort of 119 patients, 6 nonsynonymous variants in the OATP1B3 gene SLCO1B3 were identified. Individuals carrying two copies of the T allele at the 334 locus had a 2.4-fold lower value for ERMBT 1/T(max) (P = 0.001), a measure reflecting more rapid hepatic uptake. These findings suggest that differential affinities for solute carriers should be considered when selecting an appropriate phenotypic probe to allow tailored dosing of pharmaceuticals that are CYP3A4 substrates.
我们推测，基线CYP3A4活性的评估受肝细胞摄取机制中探针特异性差异的影响。在30例癌症患者中，无论其CYP3A5基因型状态如何，红霉素呼气试验（ERMBT）参数与咪达唑仑清除率之间均无显著相关性（R(2) < 0.01）。在过表达10种不同溶质载体的细胞模型中，OATP1A2（P < 0.005）和OATP1B3（P < 0.01）可显著增加红霉素摄取。咪达唑仑不是任何一种受试转运蛋白的底物。在另一组119例患者中，在OATP1B3基因SLCO1B3中鉴定出6个非同义变体。在334位点携带两个T等位基因拷贝的个体，其ERMBT 1/T(max)值低2.4倍（P = 0.001），该指标反映了更快的肝脏摄取。这些发现表明，在选择合适的表型探针以实现CYP3A4底物药物的个体化给药时，应考虑溶质载体的不同亲和力。
