Premium
Association of Liver Stiffness with Hepatic Expression of Pharmacokinetically Important Genes in Alcoholic Liver Disease
Author(s) -
Theile Dirk,
Haefeli Walter Emil,
Seitz Helmut Karl,
Millonig Gunda,
Weiss Johanna,
Mueller Sebastian
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2012.01901.x
Subject(s) - alcoholic liver disease , cirrhosis , cyp3a4 , slco1b1 , liver disease , medicine , transporter , drug , organic anion transporter 1 , organic anion transporting polypeptide , transient elastography , cyp2e1 , pharmacokinetics , pharmacology , cytochrome p450 , biology , pharmacogenetics , gene , genotype , liver fibrosis , biochemistry , metabolism
Background Enhanced drug elimination in alcoholics remains largely indefinable. In contrast, the reduced elimination of drugs in patients with advanced alcoholic liver disease ( ALD ) is normally owing to hepatic end‐stage disease such as cirrhosis. We here study the mRNA expression of various hepatic drug metabolizing enzymes and transporters in association with liver stiffness ( LS ) being a novel noninvasive parameter for the assessment of cirrhosis to unravel the dynamic relationship between ALD and determinants of pharmacokinetics such as drug metabolizing enzymes and transporters. Methods We quantified mRNA expression levels of various cytochrome P ‐450 isoenzymes ( CYP s) and drug transporters in 26 liver specimens of chronic alcoholics and 5 controls by quantitative polymerase chain reaction. In addition, liver histology, clinical data, and LS evaluated by transient elastography ( F ibroscan) were obtained. Results Eighteen patients had a normal or moderate LS < 8 kPa (69.2%), while in the remaining 8 patients (30.7%) advanced F3 or F4 fibrosis could be established with an LS > 8 kPa. Overall, CYP3A4 , CYP2E1 , and solute carrier organic anion transporter 1 B 1 ( SLCO1B1 ) were negatively correlated with increasing LS . CYP s and drug transporters tended to be up‐regulated in alcoholics without advanced fibrosis ( LS < 8.0 kPa) compared to healthy controls supporting data of boosted drug elimination in alcoholics without advanced ALD . However, in alcoholics with severely increased LS (>8 kPa), expression levels of CYP2E1 , SLC22A2 , and SLCO1B1 were significantly lower. Conclusions In conclusion, CYP s and drug transporters seem to be induced in chronic alcoholics without irreversible liver damage but decline in case of manifest cirrhosis. Our study also suggests that noninvasive measurements of LS could be useful for pharmacokinetic predictions and individualized pharmacotherapy.