Effect of high-density lipoprotein associated cyclosporine on hepatic metabolism and renal function.
Cyclosporine (CSA), in both humans and animals, is associated with plasma lipoproteins. It has been demonstrated that CSA-lipoprotein association is partly responsible for the distribution and toxicity related to CSA use. Altered plasma lipoprotein profiles are often seen in transplantation recipients undergoing CSA treatment. In the present study, daily 0.1 mg/kg intravenous injections of either high-density lipoprotein-associated CSA (HDL-CSA), plasma-associated CSA (Plasma-CSA), or CSA in Cremophor (CSA) were administered to adult male rats for 14 days. Vehicle controls included daily administrations of 0.5 ml/kg of Cremophor or saline. Serum creatinine levels, a marker of renal function, increased in rats administered Plasma-CSA as compared with control rats treated with CSA. CYP3A and CYP2C11 protein expression was suppressed by 27% and 39%, respectively, in the HDL-CSA treatment group and by 38% and 40% in the Plasma-CSA treated group as compared with CSA controls. In addition, 6beta-hydroxytestosterone, a marker of CYP3A activity, was reduced by 33% and 34% in the HDL-CSA and the Plasma-CSA treatment groups, respectively, as compared with the CSA control group. CYP2C11 activity was measured by the in vitro formation of 2alpha-hydroxytestosterone. Activity levels in rats treated with HDL-CSA and Plasma-CSA were slightly induced as compared to CSA controls, however these differences were not found to be statistically significant. In summary, Plasma-CSA treatment resulted in renal dysfunction and suppressed CYP3A and CPY2C11 protein expression. These results demonstratethat intravenous lipoprotein-associated CSA alters the metabolism of CSA in the rat differently than CSA alone.
Kim
Taekrho
T
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712-1074, USA.
Callahan
Shellie M
SM
Wasan
Kishor M
KM
Brunner
Lane J
LJ
D000818:Animals; D008076:Cholesterol, HDL / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004338:Drug Combinations; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D008076:Cholesterol, HDL; D004338:Drug Combinations; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System