P450 3A activity and cyclosporine dosing in kidney and heart transplant recipients.
Interpatient differences in the kinetics of cyclosporine appear to result in part from interindividual differences in the catalytic activity of an enzyme termed P450 3A. We investigated the relationship between P450 3A activity, as measured by the erythromycin breath test (ERMBT), and the appropriate stable daily dose of cyclosporine as currently determined by physicians at our institution. The ERMBT was administered to kidney and heart allograft recipients who had attended at least two monthly clinic visits without having their daily cyclosporine dose changed. There was a significant positive correlation between the ERMBT result and the daily cyclosporine doses (in milligrams per kilogram) in both the heart (r = 0.68; p = 0.04; n = 9) and kidney (r = 0.68; p = 0.03; n = 10) recipients. To confirm our findings, we prospectively administered the ERMBT on multiple occasions to 20 patients who were undergoing kidney transplantation. Although the transplant physicians were blinded to the ERMBT results, the test predicted the stable daily doses of cyclosporine that they ultimately prescribed to the patients (r = 0.54; p = 0.015). When data from all 39 patients were pooled and subjected to multiple regression analysis, the ERMBT was the only variable examined that significantly correlated with the stable daily cyclosporine dose (r = 0.63; p < 0.001; n = 39). In the 20 patients prospectively studied, the prescribed daily dose of cyclosporine generally decreased during the months after surgery and the percentage changes in cyclosporine daily dose correlated with changes in P450 3A activity during this period (r = 0.47; p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Turgeon
D K
DK
Department of Medicine, University of Michigan Medical Center, Ann Arbor 48109-0108.
Leichtman
A B
AB
Lown
K S
KS
Normolle
D P
DP
Deeb
G M
GM
Merion
R M
RM
Watkins
P B
PB
D000328:Adult; D001944:Breath Tests / Q000379:methods; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004334:Drug Administration Schedule; D004917:Erythromycin; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011446:Prospective Studies; D012044:Regression Analysis
D004917:Erythromycin; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1