Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6.
OBJECTIVE
Drug metabolism is influenced by liver disease because of the central role that the liver plays in metabolic activities in the body. However, it is still unclear how activities of specific drug-metabolizing enzymes are influenced by the presence and severity of liver disease. As a consequence, alteration in metabolism of specific drugs cannot be easily predicted or appropriate dosage adjustment recommendations made.


METHODS
The activities of cytochromes P450 (CYP) 2C19 and 2D6 were investigated in a group of patients with mild or moderate liver disease (n = 18) and a group of healthy control subjects (n = 10). The disposition of racemic mephenytoin for CYP2C19 and debrisoquin for CYP2D6 were characterized in plasma and urine samples collected over 192 hours.


RESULTS
The elimination of S-mephenytoin was severely reduced among patients with liver disease, resulting in a 79% decrease in plasma clearance for all patients combined. This reduction was related to the severity of disease, patients with moderate disease being affected more severely than patients with mild disease. Similar differences were observed in the urinary excretion of 4'-hydroxymephenytoin metabolite. By contrast, there was no effect on the disposition of R-mephenytoin or debrisoquin.


CONCLUSIONS
These results show selectivity in the effect of liver disease on activities of specific metabolizing enzymes, CYP2C19 being more sensitive than CYP2D6. They suggest that recommendations for modification in drug dosage in the presence of liver disease should be based on knowledge of the particular enzyme involved in metabolism of the drug. The results emphasize the need for further studies of each specific drug-metabolizing enzyme in the presence of liver disease.
University of Pittsburgh Medical Center, Department of Pharmaceutical Sciences, PA 15213-2582, USA.
A
A
Adedoyin
P A
PA
Arns
W O
WO
Richards
G R
GR
Wilkinson
R A
RA
Branch
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008617:Mephenytoin / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D013237:Stereoisomerism; D013565:Sympatholytics / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine
D000927:Anticonvulsants; D013565:Sympatholytics; C025687:4-hydroxymephenytoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D008617:Mephenytoin; D003647:Debrisoquin