Liver disease selectively modulates cytochrome P450--mediated metabolism.
BACKGROUND
The liver plays a significant role in drug metabolism; thus it would be expected that liver disease may have a detrimental effect on the activity of cytochrome P450 (CYP) enzymes. The extent to which the presence and severity of liver disease affect the activity of different individual drug-metabolizing enzymes is still not well characterized. The purpose of this study was to assess the effect of liver disease on multiple CYP enzymes by use of a validated cocktail approach.


METHODS
The participants in this investigation were 20 patients with different etiologies and severity of liver disease and 20 age-, sex-, and weight-matched healthy volunteers. Liver disease severity was categorized by use of the Child-Pugh score. All participants received a cocktail of 4 oral drugs simultaneously, caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and chlorzoxazone, as in vivo probes of the drug-metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, and CYP2E1, respectively. The primary end points were measurements of specific CYP metabolism indexes for each enzyme.


RESULTS
Mephenytoin metabolism was significantly decreased in both patients with mild liver disease (Child-Pugh score of 5/6) (-63% [95% confidence interval (CI), -86% to -40%]; P = .0003) and patients with moderate to severe liver disease (Child-Pugh score >6) (-80% [95% CI, -95% to -64%]; P = .0003). In comparison with control subjects, the caffeine metabolic ratio was 69% lower (95% CI, -85% to -54%; median, 0.14 versus 0.62; P = .0003), the debrisoquin recovery ratio was 71% lower (95% CI, -96% to -47%; median, 0.10 versus 0.65; P = .012), and the chlorzoxazone metabolic ratio was 60% lower (95% CI, -91% to -29%; median, 0.21 versus 0.83; P = .0111) in patients with moderate to severe liver disease. All 4 drugs showed significant negative relationships with the Child-Pugh score.


CONCLUSIONS
CYP enzyme activity is differentially affected by the presence of liver disease. We propose that the data can be explained by the "sequential progressive model of hepatic dysfunction," whereby liver disease severity has a differential effect on the metabolic activity of specific CYP enzymes.
Frye
Reginald F
RF
Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, USA.
Zgheib
Nathalie K
NK
Matzke
Gary R
GR
Chaves-Gnecco
Diego
D
Rabinovitz
Mordechai
M
Shaikh
Obaid S
OS
Branch
Robert A
RA
D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D002110:Caffeine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002753:Chlorzoxazone / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008617:Mephenytoin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D012720:Severity of Illness Index; D013806:Theophylline / Q000378:metabolism
D000927:Anticonvulsants; D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D009125:Muscle Relaxants, Central; D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; C025687:4-hydroxymephenytoin; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D002753:Chlorzoxazone; C021183:1,7-dimethylxanthine; D008617:Mephenytoin; D003647:Debrisoquin