Caffeine metabolism before and after liver transplantation.
OBJECTIVE
To study drug metabolism in patients before and after liver transplantation using caffeine as a probe drug. Forty-five patients undergoing liver transplantation for various liver diseases and who had well documented dossiers were selected for the study. Before the liver transplantation and 1 month, 1 year, and 6 years after liver transplantation, they were given 200 mg of caffeine by the oral route in the morning after voiding their bladder. Twenty-four-hour urine samples were collected and caffeine and metabolites were determined by HPLC: 1-methylurate (1U), 1-methylxanthine (1X), 1.7-dimethylurate (17U), 1.7-dimethylxanthine (17X), 7-methylxanthine (7X), 3-methylxanthine (3X), 1.3-dimethylurate (13U), 3.7-dimethylxanthine (37X), 1.3-dimethylxanthine (13X), 1.3.7-trimethylxanthine = caffeine (137X). Indices of enzyme activities were calculated from the following urinary elimination ratios: (AFMU+1U+1X)/17U for CYP1A2, 17U/17X for CYP2A6, 1U/1X for xanthine oxidase (XO), AFMU/(AFMU+1U+1X) for N-acetyltransferase (NAT-2).


RESULTS
Compared with results obtained in a group of 70 healthy subjects, caffeine metabolism before liver transplantation was deeply depressed with a decreased elimination rate in the case of all metabolites and a decreased CYP1A2 activity. Caffeine metabolism began to return to the control values one month after transplantation. One year and 6 years after liver transplantation, quantitatively, the metabolism of caffeine was stable and not different from control, but with qualitative modifications. CYP1A2 activity was decreased with reduced urinary elimination rates of 1X and 17X. XO and CYP2A6 activities and 1U and 17U urinary elimination rates were increased. Immunosuppressive treatment was possibly responsible for the metabolic pathway changes. Almost the same modifications were observed in 9 patients after bone marrow transplantation who had been treated with the same immunosuppressive drugs, cyclosporine and azathioprine. During severe rejection phases in 6 of the liver transplant patients, caffeine metabolism was progressively decreased when the usual liver function tests showed moderate but uniform changes.


CONCLUSIONS
Despite an apparent normal drug-metabolic function, immunosuppressive treatment induces stable variations in drugmetabolic pathways after liver transplantation which can be detected from the changes in caffeine metabolism.
Département de Pharmacologie Clinique, Faculté de Médecine, H pital Universitaire, Besançon, France.
Y C
YC
Bechtel
H
H
Lelouët
S
S
Hrusovsky
M P
MP
Brientini
G
G
Mantion
G
G
Paintaud
J P
JP
Miguet
P R
PR
Bechtel
D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D001379:Azathioprine / Q000494:pharmacology; D002110:Caffeine / Q000378:metabolism*; D016022:Case-Control Studies; D016572:Cyclosporine / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012016:Reference Values; D014498:Uracil / Q000031:analogs & derivatives / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D007166:Immunosuppressive Agents; D002110:Caffeine; D014498:Uracil; D016572:Cyclosporine; C036692:5-acetylamino-6-formylamino-3-methyluracil; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D014969:Xanthine Oxidase; D001379:Azathioprine