What changes drug metabolism in critically ill patients? Two preliminary studies in isolated human hepatocytes.
The metabolism of many drugs is abnormal in the critically ill patient. The causes of this are unknown, and investigation in patients is difficult. We therefore used isolated, cultured human hepatocytes to study the effects of hypoxia and induction on cytochrome P450 3A, the cytochrome responsible for the metabolism of many drugs. When hepatocytes were exposed to 5% oxygen, the amount of 3A produced, after induction with rifampicin, was five to 10 times less than the amount produced in 21% oxygen. In another study, we exposed isolated hepatocytes for 4 days to serum from five critically ill patients or from volunteers. At the end of this time, the functional ability of the hepatocytes to glucuronidate 14C progesterone was measured. Four of the five patients had a substance in their plasma that reduced the ability of the hepatocytes to glucuronidate progesterone. The nature of this substance and the reason that the serum from the fifth patient did not affect metabolism are unknown. This model is able to simulate the abnormalities which occur in critically ill patients. Further studies are needed to explain our observations and to identify the substances in the serum from critically ill patients that alter drug metabolism.
Park
G R
GR
Inserm U 128, Montpelier, France.
Pichard
L
L
Tinel
M
M
Larroque
C
C
Elston
A
A
Domerque
J
J
Dexionne
B
B
Maurel
P
P
D000236:Adenoma / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology; D016638:Critical Illness; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000097:blood / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D012720:Severity of Illness Index
D004364:Pharmaceutical Preparations; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating