Transiently altered acetaminophen metabolism after liver transplantation.
OBJECTIVE
Acetaminophen (INN, paracetamol) is metabolized to N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic metabolite, predominantly by cytochrome P450 (CYP) 2E1. Alterations in drug metabolism occur after organ transplantation. This study was designed to characterize acetaminophen disposition during the first 6 months after liver transplantation.


METHODS
Thirteen liver transplant patients received an oral dose of acetaminophen (500 mg) on days 2, 10, 90, and 180 after transplantation. Serial blood samples were collected for 8 hours, and urine was collected for 24 hours. Liver biopsy specimens were obtained from the donor liver during transplantation (day 0) and on days 10, 90, and 180 after transplantation.


RESULTS
There were significant time-dependent changes in acetaminophen metabolism after liver transplantation. When day 2 and day 10 were compared with day 180, the respective mean urinary recovery was 137% and 81% higher for thioether conjugates derived from NAPQI (P =.0002 and P =.01, respectively); 31% and 22% lower for acetaminophen sulfate (P =.0006 and P =.008, respectively); and 22% and 27% lower for acetaminophen glucuronide (P =.05 and P =.004, respectively). Metabolite formation clearances changed in concordance with the fractional urinary recovery. It was surprising that hepatic CYP2E1 content on day 10 after transplantation was only 20% higher, on average, than that found on day 180 (not significant). In contrast, hepatic CYP3A4 content was 984% higher, on average, when tissue from days 10 and 180 was compared after transplantation (P =.007).


CONCLUSIONS
Increased recovery of acetaminophen thioether conjugates during the first 10 days after liver transplantation was a result of impaired glucuronidation and sulfation and enhanced NAPQI formation.
Park
Jeong M
JM
Department of Pharmacy, University of Washington, Seattle, WA, USA.
Lin
Yvonne S
YS
Calamia
Justina C
JC
Thummel
Kenneth E
KE
Slattery
John T
JT
Kalhorn
Thomas F
TF
Carithers
Robert L
RL
Levy
Adam E
AE
Marsh
Christopher L
CL
Hebert
Mary F
MF
D000082:Acetaminophen / Q000493:pharmacokinetics*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016227:Benzoquinones / Q000378:metabolism; D001707:Biopsy, Needle; D001711:Biotransformation; D015153:Blotting, Western; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D007097:Imines / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged
D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C028473:N-acetyl-4-benzoquinoneimine