Effects of uremic serum and uremic toxins on hepatic uptake of digoxin.
Not only the renal clearance but also the hepatic clearance of drugs varies with the progression of renal failure. The aim of this study was to investigate the effects of human uremic serum and various uremic toxins on the hepatic uptake of digoxin (DX), a drug mainly excreted into bile in patients with severe renal failure, using isolated rat and human hepatocytes as model systems. Uremic serum inhibited the uptake of DX into rat hepatocytes in a concentration-dependent manner, whereas normal serum did not affect the uptake. In addition, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol (PC) concentration dependently inhibited the uptake. CMPF and PC at the concentration of 400 microM, which is within the plasma concentration range attained in patients with renal failure, inhibited the uptake of DX into rat hepatocytes by 27% and 23%, respectively. In human hepatocytes, 10% uremic serum, 400 microM CMPF, and 400 microM PC inhibited the uptake of DX by 23.3%, 23.4%, and 28.2%, respectively. In conclusion, our results suggest that hepatic uptake of DX is likely to be inhibited by uremic toxins, such as CMPF and PC, present in the serum of patients with renal failure.
Tsujimoto
Masayuki
M
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
Kinoshita
Yuri
Y
Hirata
Sumio
S
Otagiri
Masaki
M
Ohtani
Hisakazu
H
Sawada
Yasufumi
Y
D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D003408:Cresols / Q000097:blood* / Q000494:pharmacology; D004077:Digoxin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000097:blood* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011422:Propionates / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D006435:Renal Dialysis; D014511:Uremia / Q000097:blood* / Q000378:metabolism
D003408:Cresols; D005663:Furans; D011422:Propionates; C032538:4-cresol; D004077:Digoxin; C041693:3-carboxy-4-methyl-5-propyl-2-furanpropionic acid