9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 19-21 July 2007, Sydney, Australia

EFFECTS OF EFAVIRENZ ON LIPID METABOLISM IN APOE*3*LEIDEN hCETP DOUBLE-TRANSGENIC MICE: EVIDENCE FOR ANTAGONISM OF LXR PATHWAY

Antiviral Therapy 2007; 12(Suppl. 2):L5 (abstract no. O-03A)

OP Flint¹, A Bellamine¹, MA Noor¹, JWA van der Hoorn², HMG Princen² and RA Parker^1
1Pharmaceutical Research and Development, Bristol-Myers Squibb Co, Princeton, NJ, USA; ²TNO Biosciences, Leiden, The Netherlands

INTRODUCTION: In HAART, efavirenz (EFV) has been associated with increases in plasma HDL-cholesterol (HDLC). We observed that EFV does not directly inhibit the activity of the plasma cholesterol ester transfer protein (CETP), and proposed an alternative hypothesis that EFV down-regulates CETP expression through antagonism of the lipid transcription factor, LXR. We tested this hypothesis in vivo by administering EFV with a potent LXR agonist, T0901317, and measuring lipid metabolism and plasma CETP levels and activity in a transgenic mouse model APOE*3*Leiden hCETP.

METHODS: Forty-two male APOE*3*Leiden hCETP transgenic mice were randomized and dosed orally once daily with vehicle, EFV (25, 50 or 75 mg/kg), T0901317 (10 mg/kg), or the combination of EFV (75 mg/kg) plus T0901317 (10 mg/kg) for 2 weeks. Total plasma cholesterol, HDL-c, triglycerides, plasma CETP protein and activity were determined.

RESULTS: T0901317 increased total cholesterol (8.2–21.2 mM), CETP protein (14.5–35.2 µg/ml), and activity (0.62–1.48 µmol/ml/h), as expected. Combination with EFV abrogated T0901317 increase in total cholesterol (8.1–12.7 mM) and CETP protein (14.7–18.0 µg/ml) and activity (0.72–0.95 µmol/ml/h). EFV, T0901317 or their combination decreased HDL-C (-55%, - 43% and -68%, respectively). Plasma triglycerides were increased with T0901317 (4.7-fold), but not with EFV alone or in combination. (P<0.05 for the reported data).

CONCLUSION: In this double transgenic mouse model, EFV prevented the marked up-regulation of plasma CETP levels induced by a potent LXR agonist. EFV also blocked some of the increases in plasma lipids observed with the LXR agonist. The demonstration of in vivo functional antagonism by EFV of a major LXR response gene, CETP, which is known to regulate human lipoprotein CE/TG exchange and affect HDL-C levels, suggests a potential molecular mechanism for the influence of EFV on human lipid profiles.

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2007-07-24
O-03A

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