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Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients.

Abstract：

BACKGROUND:Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppressive drug that has reduced the rate of acute rejection episodes by more than 40% in phase III trials when added to an immunosuppression regimen of cyclosporine (CsA) and prednisone. However, RAPA treatment tends to increase lipid levels, particularly among patients with pre-existing hyperlipidemia. METHODS:To identify the metabolic pathway(s) leading to RAPA-mediated hyperlipidemia, five patients with renal transplants maintained on CsA+/-prednisone+/- azathioprine (AZA) were studied before and after 6 weeks of treatment with RAPA (off RAPA and on RAPA, respectively). Each study patient was infused with a single bolus of [2H4]-lysine to derive metabolic parameters for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry. RESULTS:Serial lipid measurements revealed that four patients displayed increased plasma triglyceride levels after RAPA treatment, which coincided with significantly higher plasma VLDL-apoB100 concentrations (21.7+/-12.1 mg/dl off RAPA vs. 38.7+/-14.8 mg/dl on RAPA, mean+/-SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL-apoB100 concentrations was due to a significant reduction in the fractional catabolic rate (FCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0.24+/-0.10 on RAPA, mean+/-SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia was due to elevated low-density lipoprotein (LDL) cholesterol levels, which coincided with a decreased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was significantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alter basal lipoprotein lipase activity in renal transplant patients in this study. CONCLUSIONS:This study indicates that for renal transplant patients in whom RAPA treatment induces hyperlipidemia, this effect is the result of reduced catabolism of apoB100-containing lipoproteins.

journal_name

Transplantation

journal_title

Transplantation

authors

Hoogeveen RC,Ballantyne CM,Pownall HJ,Opekun AR,Hachey DL,Jaffe JS,Oppermann S,Kahan BD,Morrisett JD

doi

10.1097/00007890-200110150-00011

subject

Has Abstract

pub_date

2001-10-15 00:00:00

pages

1244-50

issue

eissn

0041-1337

issn

1534-6080

journal_volume

pub_type

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Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients.