肾药物和外源性物质葡萄糖醛酸化清除率的体外-体内外推（IV-IVE）的缩放因子。
Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and xenobiotic glucuronidation clearance.
作者信息
Knights Kathleen M, Spencer Shane M, Fallon John K, Chau Nuy, Smith Philip C, Miners John O
机构信息
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia, Australia, 5001.
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
出版信息
Br J Clin Pharmacol. 2016 Jun;81(6):1153-64. doi: 10.1111/bcp.12889. Epub 2016 Mar 14.
AIM
To determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CLUGT ).
METHODS
Microsomal protein per gram of kidney (MPPGK) was determined for human 'mixed' kidney (n = 5) microsomes (MKM). The glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme source. Unbound intrinsic clearances (CLint,u,UGT ) for PRO and morphine (MOR; 3- and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro-in vivo extrapolation (IV-IVE) approaches to assess the influence of renal CLint,u,UGT on the prediction accuracy of the calculated CLUGT values of PRO and MOR.
RESULTS
MPPGK was 9.3 ± 2.0 mg g(-1) (mean ± SD). The respective rates of DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 5.2- and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only enzymes expressed in kidney. Consistent with the activity data, the abundance of each of these enzymes was greater in KCM than in KMM. The abundance of UGT1A9 in MKM (61.3 pmol mg(-1) ) was 2.7 fold higher than that reported for HLM.
CONCLUSIONS
Scaled renal PRO glucuronidation CLint,u,UGT was double that of liver. Renal CLint,u,UGT should be accounted for in the IV-IVE of UGT1A9 and considered for UGT1A6 and 2B7 substrates.
目的
确定在通过葡萄糖醛酸化作用预测总清除率（CLUGT）时纳入肾脏药物葡萄糖醛酸化清除率所需的比例因子。
方法
测定了人“混合”肾（n = 5）微粒体（MKM）中每克肾脏的微粒体蛋白（MPPGK）。测量了MKM以及配对的皮质（KCM）和髓质（KMM）微粒体对去铁酮（DEF）、丙泊酚（PRO）和齐多夫定（AZT）的葡萄糖醛酸化活性，以及每种酶来源的UGT 1A6、1A9和2B7蛋白含量。另外还测定了MKM、人肝微粒体（HLM）以及重组UGT1A9和2B7对PRO和吗啡（MOR；3 - 和6 - ）葡萄糖醛酸化的非结合内在清除率（CLint,u,UGT）。使用体外 - 体内外推法（IV - IVE）对数据进行比例换算，以评估肾脏CLint,u,UGT对PRO和MOR计算所得CLUGT值预测准确性的影响。
结果
MPPGK为9.3 ± 2.0 mg g(-1)（平均值±标准差）。KCM对DEF（UGT1A6）、PRO（UGT1A9）和AZT（UGT2B7）的葡萄糖醛酸化速率分别比KMM高1.4倍、5.2倍和10.5倍。UGT 1A6、1A9和2B7是肾脏中唯一表达的酶。与活性数据一致，这些酶在KCM中的丰度均高于KMM。MKM中UGT1A9的丰度（61.3 pmol mg(-1)）比HLM报道的高2.7倍。
结论
经比例换算后的肾脏PRO葡萄糖醛酸化CLint,u,UGT是肝脏的两倍。在UGT1A9的IV - IVE中应考虑肾脏CLint,u,UGT，对于UGT1A6和2B7的底物也应予以考虑。
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