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TRANSLATIONAL PHYSIOLOGY

Measurement of hepatic and intestinal CYP3A4 and PGP activity by combined po + iv [¹⁴C]erythromycin breath and urine test

Department of Medicine, ¹Divison of Nephrology and ²Division of Gastroenterology and Gastrointestinal Research Center, University Hospital Gasthuisberg, Leuven B-3000, Belgium

Submitted 16 January 2003 ; accepted in final form 12 May 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.

cytochrome P-450 system; multiple drug resistance gene product; breath test; renal transplantation

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