Plasma mevalonate as a measure of cholesterol synthesis in man.

Parker, Thomas S.; McNamara, Donald J.; Brown, Clinton D.; Kolb, R; Ahrens, E. H.; Alberts, Alfred W.; Tobert, Jonathan A.; Chen, J; Schepper, P. J. De

doi:10.1172/jci111495

Cited by 159 publications

(87 citation statements)

References 31 publications

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“…28 The latter measurements, however, reflect the integrated plasma concentrations of mevalonic acid and have been shown to parallel changes in cholesterol biosynthesis. 29 These results are not incompatible with the results from the present study, which demonstrate what we believe to be compensatory increases in cholesterol biosynthesis and rates of catabolism of 126 I-LDL in freshly isolated mononuclear leukocytes from patients with heterozygous FH on chronic therapy with lovastatin, but in whom the cells were studied 12 to 15 hours after the last dose of lovastatin. The present results indicate that such compensatory changes, if they occur in the liver, are insufficient to cause a loss of hypocholesterolemic efficacy in most, but not all, patients during longterm therapy with lovastatin.…”

Section: Discussionsupporting

confidence: 73%

Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.

Hagemenas

Illingworth

1989

Arteriosclerosis

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L ovastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis.1 The hypocholesterolemic effects of lovastatin in patients with primary hypercholesterolemia have been well established, 2 -10 but the extent to which this drug affects cellular cholesterol homeostasis in humans is less well delineated. Previous in vivo studies in animals and in vitro studies in cells grown in tissue culture have shown that the administration of either lovastatin or a related drug, mevastatin (compactin), results in compensatory increases in the mass of HMG CoA reductase and in the high affinity receptor-mediated degradation of 125 l-low density lipoprotein (LDL) 11 -14 ; the question of whether or not clinically effective doses of lovastatin will induce similar changes in tissues or cells isolated from hypercholesterolemic patients on chronic therapy with lovastatin has, however, not been previously examined. Kinetic studies Received May 13,1988; revision accepted December 23,1988. with radiolabeted LDL have indicated that the hypocholesterolemic effects of lovastatin in patients with heterozygous familial hypercholesterolemia result from both an increased rate of LDL catabolism and a concurrent reduction in the rate of synthesis of LDL 3 The former is believed to be due to an increased number of high affinity LDL receptors expressed on cell membranes, particularly those in the liver.Previous studies have indteated that freshly isolated human mononuctear leukocytes show changes in cholesterol homeostasis that parallel those known to occur in the liver. 16 -18 For example, the rates of cholesterol synthesis and high affinity receptor-mediated degradation of I 12S -LDL in freshly isolated mononuctear leukocytes from patients with heterozygous familial hypercholesterolemia (FH) were both increased during therapy with the bile acid sequestrant colestipol.15 Similarty, dietary cholesterol has been shown to depress cholesterol synthesis or HMG CoA reductase activity in freshly isolated mononuclear leukocytes.1718 Both of these effects parallel those that are known to occur in the liver.In the present study, we utilized freshly isolated mononuclear leukocytes to examine whether therapy with lovastatin influences cholesterol homeostasis in patients with heterozygous FH treated with increasing doses of lovastatin. Methods SubjectsThe 23 adult patients who participated in this study were diagnosed as having heterozygous FH on the basis of persistent primary hypercholesterolemia greater than 355 by guest on May 12, 2018 http://atvb.ahajournals.org/ Downloaded from

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Section: Discussionsupporting

confidence: 73%

Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.

Hagemenas

Illingworth

1989

Arteriosclerosis

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“…In the case of cholesterol precursor measurement, the following precursors have been determined: mevalonic acid in blood plasma and 24-hour collections of urine 18 ; isoprene in breath 19 ; squalene and lathosterol in blood plasma or bile [20][21] . The concentrations of metabolites can provide relative rates of cholesterol synthesis ("snapshots") during time periods in individuals or across treatment groups.…”

Section: Methods For Determination Of Cholesterol Synthesis and Absormentioning

confidence: 99%

Hypocholesterolemia in Clinically Serious Conditions - Review

Vyroubal¹,

Chiarla²,

Giovannini³

et al. 2008

BIOMED PAP

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Background:Cholesterol is an essential component of cell membranes, precursor of steroids, biliary acids and other components of serious importance in live organism. Cholesterol synthesis is a complicated and energy-demanding process. Real daily need of cholesterol and mechanisms of decline cholesterol levels in critical ill are unknown. During stressful situations a signifi cant hypocholesterolaemia may be found. Hypocholesterolemia has been known for a number of years to be a signifi cant prognostic indicator of increased morbidity and mortality connected with a whole spectrum of pathological conditions. The aim of article is the elucidation of the role and importance of hypocholesterolaemia during the intensive care. . Methods and Results:We examined studies that are engaged in problems of hypocholesterolemia in critically ill. Very low levels of total as well as LDL cholesterol are most frequently found in serious polytrauma, after extensive surgery, in serious infections, in protracted hypovolemic shock. It is still not clear whether hypocholesterolemia refl ects only a serious metabolic disorder, which results from a life-threatening condition, or whether it has an active role in evolution and outcome.Conclusions: Hypocholesterolemia is commonly observed in critically ill patients. Nevertheless, it is not known whether it is a secondary manifestation of disease, or whether it actively contributes to deterioration of the disease. Although the contribution of hypocholesterolemia to mortality is modest compared with known risk factors such as increased severity of illness and the development of nosocomial infection, low serum lipid concentrations represent a potential therapeutic target in sepsis.

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“…Plasma MVA concentration has been shown to be a good index of the in vivo rate of cholesterol synthesis. 5) Despite the importance of HMG-CoA reductase inhibitors in the management of dyslipidemia, the relationship between drug exposure and the extent of HMG-CoA inhibition has not been elucidated. In general, peak cholesterol biosynthesis occurs at night, 6) suggesting that the hypocholesterolemic effects of HMG-CoA reductase inhibitors are stronger after evening administration than after morning administration.…”

mentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Rosuvastatin Using an Extension of the Indirect Response Model by Incorporating a Circadian Rhythm

Aoyama

Omori

Watabe

et al. 2010

Biological & Pharmaceutical Bulletin

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In 2004, the United States Food and Drug Administration issued a "critical path" document for characterizing modelbased drug development as the development and application of pharmacostatistical models of drug efficacy and safety from preclinical and clinical data to improve drug development knowledge management and decision making.1,2) Pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation also enable the prediction of the effects of a medicine in various situations in clinical practice. The effective dosage regimen for acetaminophen in chronic pain patients was suggested by PK/PD modeling and simulation.3) The development of a safe, effective dosage regimen for sotalol was based on population PK/PD modeling and simulation.4) The PK/PD analysis of sotalol suggested a dosage regimen based on age and body weight. Thus PK/PD modeling and simulation provide a useful tool that is applicable in clinical practice.Rosuvastatin is a highly effective inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase. HMG-CoA reductase converts HMG-CoA to mevalonic acid (MVA). The inhibition of HMG-CoA reductase, which catalyzes the rate-limiting step of cholesterol biosynthesis in the liver, causes a decrease in the concentration of low-density lipoprotein cholesterol (LDL-C). The reduction in intracellular cholesterol concentration induces a subsequent upregulation of LDL-C receptors on the surface of hepatocytes, which results in an enhanced extraction of LDL-C from the blood and a decreased concentration of circulating LDL-C. MVA that is produced by the action of HMG-CoA reductase on HMG-CoA is the precursor of cholesterol. Plasma MVA concentration has been shown to be a good index of the in vivo rate of cholesterol synthesis.5) Despite the importance of HMG-CoA reductase inhibitors in the management of dyslipidemia, the relationship between drug exposure and the extent of HMG-CoA inhibition has not been elucidated. In general, peak cholesterol biosynthesis occurs at night, 6) suggesting that the hypocholesterolemic effects of HMG-CoA reductase inhibitors are stronger after evening administration than after morning administration. However, robust trials are necessary to determine the best administration time to achieve optimal LDL-C lowering for rosuvastatin. 7) PK/PD modeling and simulation provide information on the relationship of the dosage regimen and the response to rosuvastatin. However, there are as yet no reports on a PK/PD model of rosuvastatin.The aims of this study were to define the PK/PD model of rosuvastatin and to predict the response to rosuvastatin using simulated plasma MVA concentration in various dosage regimens such as poor compliance, and morning and evening dosage of rosuvastatin. Moreover, to clarify the PK parameter affecting the response to rosuvastatin, useful information was provided in clinical practice. MATERIALS AND METHODS Data SourceThe plasma rosuvastatin and MVA concentrations reported by Martin et al. 8) were used as the source of PK/PD modeling data. Graphs of concentration-tim...

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Plasma mevalonate as a measure of cholesterol synthesis in man.

Cited by 159 publications

References 31 publications

Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.

Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.

Hypocholesterolemia in Clinically Serious Conditions - Review

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Rosuvastatin Using an Extension of the Indirect Response Model by Incorporating a Circadian Rhythm

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