Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis.
The small intestine and liver express high levels of cytochrome P450 3A (CYP3A), an enzyme subfamily that contributes significantly to drug metabolism. In patients with cirrhosis, reduced metabolism of drugs is typically attributed to decreased liver function, but it is unclear whether drug metabolism in the intestine is also compromised. In this study, we compared CYP3A protein expression and in vitro midazolam hydroxylation in duodenal mucosal biopsies from subjects with normal liver function (controls; n = 20) and subjects with various levels of severity of cirrhosis (n = 23). In samples from subjects with cirrhosis, duodenal CYP3A expression and total midazolam hydroxylation were lower by 47 and 34%, respectively, as compared with samples from controls. Greater decreases in CYP3A expression were seen in subjects with more severe cirrhosis. Therefore, patients with advanced cirrhosis may have greater drug exposure following oral dosing as a result of both impaired liver function and decreased intestinal CYP3A expression and activity.
McConn
D J
DJ
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
Lin
Y S
YS
Mathisen
T L
TL
Blough
D K
DK
Xu
Y
Y
Hashizume
T
T
Taylor
S L
SL
Thummel
K E
KE
Shuhart
M C
MC
D000328:Adult; D000368:Aged; D002384:Catalysis / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000032:analysis / Q000096:biosynthesis*; D004386:Duodenum / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged
D051544:Cytochrome P-450 CYP3A; D008874:Midazolam