Prediction of Human Drug Clearance by Multiple Metabolic Pathways: Integration of Hepatic and Intestinal Microsomal and Cytosolic Data
Prediction of Human Drug Clearance by Multiple Metabolic Pathways: Integration of Hepatic and Intestinal Microsomal and Cytosolic Data
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DOI：
10.1124/dmd.110.036566
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发表时间：
2011-05-01
影响因子：
3.9
通讯作者：
Galetin, Aleksandra
中科院分区：
文献类型：
--
作者：
Cubitt, Helen E.;Houston, J. Brian;Galetin, Aleksandra
本研究使用不同的体外系统评估了雷洛昔芬、槲皮素、沙丁胺醇和曲格列酮的肝和肠葡萄糖醛酸化、硫酸化和细胞色素P450（P450）代谢。通过结合代谢和P450代谢的分数估计在肝脏和肠道中，并评估多种代谢途径对清除率预测准确性的重要性。测定了人肠和肝胞液中的体外固有硫酸化清除率（克林特，SULT），并与肝和肠微粒体葡萄糖醛酸化（克林特，UGT）和P450清除率（克林特，UGT）进行了比较。根据已发表的数据，估算了80.7 mg/g肝脏和18 mg/g肠的肝脏和肠细胞溶质比例因子。缩放克林特，SULT范围为0.7 - 11.4 ml。min（-1）。g（-1）肝脏和0.1和3.3 ml . min（-1）。g（-1）肠（沙丁胺醇和槲皮素是极端）。沙丁胺醇是唯一一种具有高度硫酸化的化合物（肝脏和肠道的总克林特分别为51%和28%），也具有显著的肾脏清除率（观察到的血浆清除率的26-57%）。相比之下，槲皮素的清除主要是由葡萄糖醛酸化。与仅基于主要途径的预测（22-36%）相比，通过多种途径代谢的药物（雷洛昔芬和曲格列酮）证明，使用所有肝脏途径的数据（观察到的清除率的44-86%）可改善静脉内清除率的预测。无肠道首过的假设导致雷洛昔芬、曲格列酮和槲皮素的口服清除率预测不足（分别为观察值的3-22%）。通过估计肠道利用率解释肠道对口服清除率的贡献，提高了雷洛昔芬和曲格列酮的预测准确度（在观察值的2.5倍以内）。目前的研究结果强调了肝和肠结合对于体外-体内外推代谢清除的重要性。
The current study assesses hepatic and intestinal glucuronidation, sulfation, and cytochrome P450 (P450) metabolism of raloxifene, quercetin, salbutamol, and troglitazone using different in vitro systems. The fraction metabolized by conjugation and P450 metabolism was estimated in liver and intestine, and the importance of multiple metabolic pathways on accuracy of clearance prediction was assessed. In vitro intrinsic sulfation clearance (CLint, SULT) was determined in human intestinal and hepatic cytosol and compared with hepatic and intestinal microsomal glucuronidation (CLint, UGT) and P450 clearance (CLint, CYP) expressed per gram of tissue. Hepatic and intestinal cytosolic scaling factors of 80.7 mg/g liver and 18 mg/g intestine were estimated from published data. Scaled CLint, SULT ranged between 0.7 and 11.4 ml . min(-1) . g(-1) liver and 0.1 and 3.3 ml . min(-1) . g(-1) intestine (salbutamol and quercetin were the extremes). Salbutamol was the only compound with a high extent of sulfation (51 and 28% of total CLint for liver and intestine, respectively) and also significant renal clearance (26-57% of observed plasma clearance). In contrast, the clearance of quercetin was largely accounted for by glucuronidation. Drugs metabolized by multiple pathways (raloxifene and troglitazone) demonstrated improved prediction of intravenous clearance using data from all hepatic pathways (44-86% of observed clearance) compared with predictions based only on the primary pathway (22-36%). The assumption of no intestinal first pass resulted in underprediction of oral clearance for raloxifene, troglitazone, and quercetin (3-22% of observed, respectively). Accounting for the intestinal contribution to oral clearance via estimated intestinal availability improved prediction accuracy for raloxifene and troglitazone (within 2.5-fold of observed). Current findings emphasize the importance of both hepatic and intestinal conjugation for in vitro-in vivo extrapolation of metabolic clearance.