Early postoperative erythromycin breath test correlates with hepatic cytochrome P4503A activity in liver transplant recipients.
BACKGROUND
Interindividual variation in the pharmacokinetics of the immunosuppressive agents cyclosporine (INN, ciclosporin) and tacrolimus may result from differences in the activity of cytochrome P4503A (CYP3A). The erythromycin breath test is an in vivo assay of hepatic CYP3A activity, but the method has never been directly validated. The aim of the study was to investigate whether an early postoperative erythromycin breath test correlated with the hepatic CYP3A protein level and catalytic activity in liver transplant recipients.


METHODS
In 18 liver transplant recipients, the erythromycin breath test was performed within 2 hours after transplantation. A graft biopsy was obtained during surgery and analyzed for the CYP3A protein level by Western blotting and for CYP3A activity with erythromycin demethylation and testosterone 6beta- hydroxylation assays.


RESULTS
The erythromycin breath test values ranged from 0.14% to 1.65% of carbon 14 per hour, and the CYP3A protein level ranged from 732 to 7822 as measured by optical density. The in vitro catalytic activity determined by the erythromycin demethylation assay ranged from 94 to 902 disintegrations per minute per 5 minutes per milligram of protein, and the activity determined by testosterone 6beta-hydroxylation ranged from 0.030 to 0.627 nmol per minute per milligram of protein. Significant correlation was demonstrated between the erythromycin breath test and both the erythromycin demethylation (Spearman correlation coefficient: R = 0.76, R (2) = 0.57; P =.0004) and the testosterone 6beta-hydroxylation (Spearman correlation coefficient: R = 0.79, R (2) = 0.63; P =.0001) assays. The erythromycin breath test also correlated with the CYP3A protein level (Spearman correlation coefficient: R = 0.60, R (2) = 0.36; P =.01).


CONCLUSIONS
Our data support the erythromycin breath test as a specific in vivo assay of CYP3A activity in humans. The test is applicable in liver transplant recipients in the early postoperative phase. Future studies should evaluate the clinical usefulness of an early postoperative erythromycin breath test as a predictor of cyclosporine-tacrolimus pharmacokinetics in liver transplantation.
Schmidt
L E
LE
Department of Hepatology A, Rigshospitalet, Copenhagen, Denmark. lars.schmidt@dadlnet.dk
Olsen
A K
AK
Stentoft
K
K
Rasmussen
A
A
Kirkegaard
P
P
Dalhoff
K
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D004917:Erythromycin / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating