Drug biotransformation by human hepatocytes. In vitro/in vivo metabolism by cells from the same donor.
OBJECTIVE
Cultured human hepatocytes are considered a close model to human liver. However, the fact that hepatocytes are placed in a microenvironment that differs from that of the cell in the liver raises the question: to what extent does drug metabolism in vitro reflect that of the liver in vivo? This issue was examined by investigating the in vitro and in vivo metabolism of aceclofenac, an analgesic/anti-inflammatory drug.


METHODS
Hepatocytes isolated from programmed liver biopsies were incubated with aceclofenac, and the metabolites formed were investigated by HPLC. During the course of clinical recovery, patients were given the drug, and the metabolites, largely present in the urine, were analyzed. In vitro and in vivo data of the same individual were compared.


RESULTS
The relative abundance of oxidized metabolites in vitro (i.e. 4'OH-aceclofenac + 4'OH-diclofenac vs. total hydroxylated metabolites; Spearman's p = 0.855), as well the hydrolysis of aceclofenac (4'OH-diclofenac vs. 4'OH-aceclofenac + 4'OH-diclofenac; p = 0.691) correlated well with in vivo data. The conjugation of the drug in vitro (24.6 +/- 7.6%) was lower than that in vivo (44.9 +/- 5.3%). The rate of 4'OH-aceclofenac formation in vitro correlated with the amount of metabolites excreted in urine after 16 h (p = 0.95).


CONCLUSIONS
The in vitro/in vivo metabolism of the drug was surprisingly similar in each patient. The variability observed in vitro reflected an existing phenotypic variability among donors.
Ponsoda
X
X
Unidad de Hepatología Experimental, Centro de Investigación, Hospital Universitario la Fe, Valencia, Spain.
Pareja
E
E
Gómez-Lechón
M J
MJ
Fabra
R
R
Carrasco
E
E
Trullenque
R
R
Castell
J V
JV
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001711:Biotransformation; D002478:Cells, Cultured; D004008:Diclofenac / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; C056498:aceclofenac