Cyclosporine A and Rapamycin induce in vitro cholesteryl ester transfer protein activity, and suppress lipoprotein lipase activity in human plasma.

Abstract

PURPOSE:

Cyclosporine A (CsA), Rapamycin (RAPA), Tacrolimus (FK-506) and Mycophenolate mofetil (MMF) are immunosuppressants that are widely used in solid organ transplant patients. However, some of these drugs have been reported to cause dyslipidemia in patients. Our aim was to determine the effects of these drugs on in vitro cholesteryl ester transfer protein (CETP), hepatic lipase (HL) and lipoprotein lipase (LPL) activity within human plasma.

METHODS:

We measured CETP activity in human normolipidemic plasma with and without drug treatment, by measuring the incorporation of labeled cholesteryl ester into lipoproteins. To further confirm the result, we also measured recombinant CETP (rCETP) activity with and without drug treatment. We measured HL and LPL activity in post-heparin normal human plasma in the presence and absence of the drugs by measuring the release of fatty acids from radiolabeled triolein.

RESULTS:

We found an increase in CETP activity in human normolipidemic plasma and rCETP treated with CsA and RAPA. By contrast, CETP activity was not altered significantly in the presence of FK-506 and MMF. LPL activity in post-heparin normal human plasma was suppressed following the co-incubation with CsA, RAPA, FK-506 or MMF whereas HL activity remained unaffected.

CONCLUSIONS:

The increase in CETP activity and suppression in LPL activity following CsA and RAPA treatment observed in the present study may be associated with elevated LDL cholesterol levels and hypertriglyceridemia seen in patients administered these drugs.

• Authors: Rita Tory, Kristina Sachs-Barrable, John S Hill, Kishor M Wasan
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 358 Issue 1-2 Pg. 219-23 (Jun 24 2008) ISSN: 0378-5173 [Print] Netherlands
• PMID: 18448283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CETP protein, human
• Cholesterol Ester Transfer Proteins
• Enzyme Inhibitors
• Fatty Acids
• Immunosuppressive Agents
• Recombinant Proteins
• Cyclosporine
• Lipoprotein Lipase
• Mycophenolic Acid
• Sirolimus
• Tacrolimus

Topics

• Cholesterol Ester Transfer Proteins (blood, metabolism, pharmacology)
• Cyclosporine (pharmacology)
• Enzyme Inhibitors
• Fatty Acids (chemistry)
• Humans
• Immunosuppressive Agents (pharmacology)
• Lipoprotein Lipase (antagonists & inhibitors, blood)
• Liver (drug effects, enzymology)
• Mycophenolic Acid (analogs & derivatives, pharmacology)
• Recombinant Proteins (blood)
• Sirolimus (pharmacology)
• Spectrometry, Fluorescence
• Tacrolimus (pharmacology)