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Cytochrome P450 3A4 and P‐glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin
Author(s) -
Paine Mary F.,
Wagner David A.,
Hoffmaster Keith A.,
Watkins Paul B.
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.128387
Subject(s) - erythromycin , cyp3a4 , oral administration , rifampicin , pharmacology , antibacterial agent , cyp3a , medicine , pharmacokinetics , antibiotics , gastroenterology , chemistry , cytochrome p450 , metabolism , biochemistry
Background 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. Methods After an overnight fast, 14 young healthy volunteers (5 women and 9 men) received the ERMBT IV (0.07 μmol, 3 μCi), 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. Results 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 ≤ .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 ≥ .07). In addition, troleandomycin had no effect on erythromycin transport in Caco‐2 cells ( P ≥ .20). Conclusions 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. Clinical Pharmacology & Therapeutics (2002) 72 , 524–535; doi: 10.1067/mcp.2002.128387