BACKGROUND: Quantification of plasma levels of an early and late intermediate on the cholesterol pathway, mevalonic acid (MVA) and lathosterol respectively, provides a useful method of estimating cholesterol synthesis in humans. The aim of this study was to assess further their roles as indices of cholesterol synthesis under non-steady-state conditions. METHODS: The short-term effects of pharmacological inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase on both variables were determined in four normolipidaemic subjects during and after treatment with simvastatin 20 mg daily. Plasma MVA was measured using gas chromatography-mass spectrometry, and lathosterol using gas chromatography. RESULTS: A single dose of 20 mg of simvastatin decreased plasma MVA after 2 h and decreased the lathosterol-cholesterol (L/C) ratio after 4 h. Treatment with simvastatin 20 mg daily for 9 days decreased both variables by approximately 50%, the nadir of plasma MVA occurring on the second day and of the L/C ratio on the fifth day, and resulted in a 39% reduction in low-density lipoprotein (LDL)-cholesterol. After discontinuing simvastatin, there were rebounds in plasma MVA and the L/C ratio to above basal levels but not in LDL cholesterol or apolipoprotein B (apoB), the latter continuing to decrease for a further 2 days. CONCLUSION: These results suggest that simvastatin rapidly down-regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.
BACKGROUND: Quantification of plasma levels of an early and late intermediate on the cholesterol pathway, mevalonic acid (MVA) and lathosterol respectively, provides a useful method of estimating cholesterol synthesis in humans. The aim of this study was to assess further their roles as indices of cholesterol synthesis under non-steady-state conditions. METHODS: The short-term effects of pharmacological inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase on both variables were determined in four normolipidaemic subjects during and after treatment with simvastatin 20 mg daily. Plasma MVA was measured using gas chromatography-mass spectrometry, and lathosterol using gas chromatography. RESULTS: A single dose of 20 mg of simvastatin decreased plasma MVA after 2 h and decreased the lathosterol-cholesterol (L/C) ratio after 4 h. Treatment with simvastatin 20 mg daily for 9 days decreased both variables by approximately 50%, the nadir of plasma MVA occurring on the second day and of the L/C ratio on the fifth day, and resulted in a 39% reduction in low-density lipoprotein (LDL)-cholesterol. After discontinuing simvastatin, there were rebounds in plasma MVA and the L/C ratio to above basal levels but not in LDL cholesterol or apolipoprotein B (apoB), the latter continuing to decrease for a further 2 days. CONCLUSION: These results suggest that simvastatin rapidly down-regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.
Authors: Vladimír Hrabovský; Alice Mendlová; Zdeněk Zadák; Vladimír Bláha; Radomír Hyšpler; Alena Tichá; Zdeněk Svagera Journal: Wien Klin Wochenschr Date: 2012-11-20 Impact factor: 1.704
Authors: Harri Juhani Saarinen; Chaiyasit Sittiwet; Piia Simonen; Markku J Nissinen; Ulf-Håkan Stenman; Helena Gylling; Ari Palomäki Journal: J Investig Med Date: 2017-08-11 Impact factor: 2.895