Paine Mary F, Wagner David A, Hoffmaster Keith A, Watkins Paul B
Department of Pharmacology, University of Michigan, Ann Arbor, USA.
Clin Pharmacol Ther. 2002 Nov;72(5):524-35. doi: 10.1067/mcp.2002.128387.
The intravenous (14)C-erythromycin breath test (ERMBT(IV)) does not measure aggregate liver and intestinal cytochrome P450 (CYP) 3A4 activity. Accordingly, we evaluated an oral stable-labeled ((13)C) formulation of the test (ERMBT(oral)) as an alternative CYP3A4 phenotyping probe.
After an overnight fast, 14 young healthy volunteers (5 women and 9 men) received the ERMBT(IV) (0.07 micromol, 3 muCi), followed by the ERMBT(oral) (500 mg). The next morning, the CYP3A4 inhibitor troleandomycin (500 mg) was given, and both ERMBTs were repeated. After at least 24 hours, the CYP3A4 and P-glycoprotein inducer rifampin (600 mg; INN, rifampicin) was given daily for 7 days, and both ERMBTs were repeated 24 hours after the last dose of rifampin. Plasma samples were collected for 10 hours with each administration of the ERMBT(oral), and erythromycin levels were measured by liquid chromatography-mass spectrometry. Finally, the effect of troleandomycin on erythromycin transport was examined in Caco-2 cell monolayers.
Compared with baseline values, the median ERMBT(IV) and ERMBT(oral) results and erythromycin apparent oral clearance (CL/F) all significantly decreased, by at least 70%, with troleandomycin treatment (P =.001 for each comparison). With rifampin treatment, the median ERMBT(IV) result and CL/F increased 2-fold (P < or =.01), but the median ERMBT(oral) result was unchanged (P =.30). There were no rank-order correlations between the ERMBT(IV) and ERMBT(oral) results or between either ERMBT result and CL/F within each treatment group (P > or =.07). In addition, troleandomycin had no effect on erythromycin transport in Caco-2 cells (P > or =.20).
The ERMBT(oral) was influenced by processes in addition to intestinal and hepatic CYP3A4 activity and therefore did not provide a straightforward measure of aggregate CYP3A4 phenotype. The erythromycin-rifampin interaction cannot be attributed to CYP3A4 induction alone and probably also reflected intestinal P-glycoprotein induction.
静脉注射（14）C-红霉素呼气试验（ERMBT（IV））无法测量肝脏和肠道细胞色素P450（CYP）3A4的总活性。因此，我们评估了该试验的口服稳定同位素标记（（13）C）制剂（ERMBT（口服））作为CYP3A4表型分析的替代探针。
14名年轻健康志愿者（5名女性和9名男性）隔夜禁食后，先接受ERMBT（IV）（0.07微摩尔，3微居里），随后接受ERMBT（口服）（500毫克）。次日早晨，给予CYP3A4抑制剂醋竹桃霉素（500毫克），并重复两项ERMBT试验。至少24小时后，每日给予CYP3A4和P-糖蛋白诱导剂利福平（600毫克；国际非专利名称，利福平），共7天，在最后一剂利福平后24小时重复两项ERMBT试验。每次给予ERMBT（口服）后采集10小时的血浆样本，采用液相色谱-质谱法测定红霉素水平。最后，在Caco-2细胞单层中检测醋竹桃霉素对红霉素转运的影响。
与基线值相比，醋竹桃霉素治疗后，ERMBT（IV）和ERMBT（口服）结果的中位数以及红霉素口服表观清除率（CL/F）均显著降低，至少降低70%（每次比较P = 0.001）。利福平治疗后，ERMBT（IV）结果的中位数和CL/F增加了2倍（P≤0.01），但ERMBT（口服）结果的中位数未改变（P = 0.30）。各治疗组中，ERMBT（IV）和ERMBT（口服）结果之间，以及任一ERMBT结果与CL/F之间均无等级相关性（P≥0.07）。此外，醋竹桃霉素对Caco-2细胞中红霉素的转运无影响（P≥0.20）。
ERMBT（口服）除受肠道和肝脏CYP3A4活性影响外，还受其他过程影响，因此不能直接测量CYP3A4的总表型。红霉素-利福平相互作用不能仅归因于CYP3A4诱导，可能还反映了肠道P-糖蛋白诱导。
