Lemahieu W P D, Maes B D, Ghoos Y, Rutgeerts P, Verbeke K, Vanrenterghem Y
Department of Medicine, University Hospital, Gasthuisberg, B-3000 Leuven, Belgium.
Am J Physiol Gastrointest Liver Physiol. 2003 Sep;285(3):G470-82. doi: 10.1152/ajpgi.00028.2003.
The aim of the present study was to develop a test for measuring hepatic and intestinal removal of cytochrome p-450 3A4 (CYP3A4)- and P-glycoprotein (PGP)-dependent xenobiotics that would be applicable for clinical use in humans. Orally and intravenously administered [N-methyl-14C]erythromycin was used for evaluation of 14C-labeled excretion dynamics in breath and urine. Simultaneous breath and urine test measurements were performed in 32 healthy volunteers and in 23 renal transplant recipients. Mathematical analysis of the excretion rate of labeled CO2 in breath and labeled carbon in urine resulted in 1). separation of both CYP3A4 and PGP activity in the liver and the intestinal mucosa and 2). numerical calculation of the dynamics of the different processes. The test was sufficiently sensitive to detect theoretically predicted process-specific pharmacological modulations by different drugs in healthy volunteers and after recent renal transplantation. It is concluded that the combined oral and intravenous erythromycin breath and urine test is a reliable and noninvasive test to measure phenotypic intestinal and hepatic CYP3A4 and PGP activity and may be a promising tool for prediction of drug interactions and dose adjustment of many pharmacotherapeutics in clinical practice, e.g., immunosuppressive agents after renal transplantation.
本研究的目的是开发一种用于测量细胞色素P-450 3A4（CYP3A4）和P-糖蛋白（PGP）依赖性外源性物质肝肠清除率的检测方法，该方法适用于人类临床应用。口服和静脉注射的[N-甲基-14C]红霉素用于评估呼气和尿液中14C标记的排泄动力学。对32名健康志愿者和23名肾移植受者进行了同步呼气和尿液检测。对呼气中标记二氧化碳的排泄率和尿液中标记碳的排泄率进行数学分析，结果如下：1）区分肝脏和肠黏膜中CYP3A4和PGP的活性；2）对不同过程的动力学进行数值计算。该检测方法灵敏度足够高，能够在健康志愿者和近期肾移植后检测到不同药物对理论预测的特定过程的药理调节作用。结论是，口服和静脉联合使用红霉素呼气和尿液检测是一种可靠的非侵入性检测方法，可用于测量肠道和肝脏中CYP3A4和PGP的表型活性，可能是临床实践中预测药物相互作用和调整许多药物治疗剂量（如肾移植后的免疫抑制剂）的一种有前景的工具。
