Relation between circadian patterns in levels of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men

Bremner, W. F.; Sothern, Robert B.; Kanabrocki, Eugene L.; Ryan, M.; McCormick, James B.; Dawson, Susan; Connors, Eileen S.; Rothschild, R.M.; Third, Jane L.H.C.; Vahed, Sabera; Nemchausky, Bernard M.; Shirazi, Parvez; Olwin, John H.

doi:10.1016/s0002-8703(00)90324-7

Cited by 80 publications

(54 citation statements)

References 59 publications

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“…Potential mechanisms for this behavior include enterohepatic recirculation of intact drug eliminated by hepatic efflux or circadian variation in endogenous levels of plasma proteins or lipoproteins to which odanacatib binds. Lipoprotein binding can alter the PK of lipophilic drugs (Wasan et al, 2008), and the magnitude of the variation observed in this study with odanacatib (approximately 10% of total distribution volume) is consistent with the diurnal variation observed in lipoprotein levels (Bremner et al, 2000). Overall, these fluctuations are relatively small and unlikely to be clinically relevant for a drug that will be administered chronically.…”

Section: Discussionsupporting

confidence: 80%

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women

Zajic

Rossenu

Hreniuk

et al. 2016

Drug Metabolism and Disposition

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A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable 13 C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was ∼100 liters. The clearance was ∼0.8 l/h (13 ml/min), supporting that odanacatib is a low-extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to C max in some subjects.

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Section: Discussionsupporting

confidence: 80%

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women

Zajic

Rossenu

Hreniuk

et al. 2016

Drug Metabolism and Disposition

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“…8 This is supported by other smaller studies. 7,16 As well as seasonal effects, variable reports exist of a diurnal pattern in fibrinogen 12,22,23 and D-dimer, 24 -26 whereas t-PA shows a morning peak with levels that tend to decline during the day; 12,24,27,28 vWF has been reported to show no diurnal variation in 1 small study. 28 Diurnal variation may be an important source of heterogeneity or bias, and standardization for sampling time may be important in populationbased studies, as well as in using these variables for additional coronary heart disease risk prediction in individuals.…”

Section: Clinical Perspective P 1003mentioning

confidence: 92%

Diurnal, Seasonal, and Blood-Processing Patterns in Levels of Circulating Fibrinogen, Fibrin D-Dimer, C-Reactive Protein, Tissue Plasminogen Activator, and von Willebrand Factor in a 45-Year-Old Population

et al. 2007

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Background-Circulating levels of fibrinogen, fibrin D-dimer, C-reactive protein (CRP), tissue plasminogen activator antigen (t-PA) and von Willebrand factor are associated with incident coronary heart disease. We describe cross-sectional diurnal, seasonal, and blood-processing patterns for these variables, and assess whether they represent important sources of variability that should be taken into account in epidemiological studies or for additional risk prediction in individuals. Methods and Results-A total of 9377 men and women aged 45 years were visited in their homes and blood-sampled for fibrinogen, D-dimer, CRP, t-PA, and von Willebrand factor. These variables were examined in relation to the time of blood sample collection, day of the year, and delay in processing. All variables exhibited statistically significant diurnal sinusoidality (PՅ0.02). Our models predicted a peak rise for fibrinogen and von Willebrand factor at midday, with overall diurnal variations of 3% and 10%, respectively, after adjustment for standard cardiovascular risk factors. D-dimer exhibited a peak at 14:00 hours, CRP at 15:00 hours, and t-PA at 10:00 hours with diurnal variations of 10%, 34%, and 55%, respectively, after full adjustment. All variables except CRP showed seasonal heterogeneity. Greater delays in processing blood samples were associated with higher levels of t-PA in particular. The proportion of variation attributed to the diurnal, seasonal, and processing effects was 2% for fibrinogen and von Willebrand factor; 9% for D-dimer, 1% for CRP, and 16% for t-PA. Conclusions-Temporal variations are important sources of heterogeneity that may bias the analysis of epidemiological studies and coronary heart disease risk prediction in individuals. Sample-processing delay is particularly important for t-PA.

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“…[17][18][19][20][21] It has been suggested that it is attributed primarily to the diurnal variations of cardiovascular parameters, such as sympathetic nerve activity, blood pressure, and heart rate, in addition to variations in plasma lipid, platelets, coagulation factors, or endothelial dysfunction. [22][23][24][25][26][27][28][29] However, it is unknown whether the diurnal variation of cardiovascular parameters is controlled primarily by circadian clock genes or influenced secondarily by external factors. The aim of the present study is to investigate whether there are alterations in endothelial functions in a mouse model with Per2 mutation and whether the endothelial functional changes are associated with the metabolic cardiovascular risk factors, the phenotype observed in the CLOCK and BMAL1 mutant mice.…”

Section: Clinical Perspective P 2195mentioning

confidence: 99%

Mutation of the Circadian Clock Gene Per2 Alters Vascular Endothelial Function

et al. 2007

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Background-The circadian clock regulates biological processes including cardiovascular function and metabolism. In the present study, we investigated the role of the circadian clock gene Period2 (Per2) in endothelial function in a mouse model. Methods and Results-Compared with the wild-type littermates, mice with Per2 mutation exhibited impaired endotheliumdependent relaxations to acetylcholine in aortic rings suspended in organ chambers. During transition from the inactive to active phase, this response was further increased in the wild-type mice but further decreased in the Per2 mutants. The endothelial dysfunction in the Per2 mutants was also observed with ionomycin, which was improved by the cyclooxygenase inhibitor indomethacin. No changes in the expression of endothelial acetylcholine-M 3 receptor or endothelial nitric oxide synthase protein but increased cyclooxygenase-1 (not cyclooxygenase-2) protein levels were observed in the aortas of the Per2 mutants. Compared with Per2 mutants, a greater endothelium-dependent relaxation to ATP was observed in the wild-type mice, which was reduced by indomethacin. In quiescent aortic rings, ATP caused greater endothelium-dependent contractions in the Per2 mutants than in the wild-type mice, contractions that were abolished by indomethacin. The endothelial dysfunction in the Per2 mutant mice is not associated with hypertension or dyslipidemia. Conclusions-Mutation in the Per2 gene in mice is associated with aortic endothelial dysfunction involving decreased production of NO and vasodilatory prostaglandin(s) and increased release of cyclooxygenase-1-derived vasoconstrictor(s). The results suggest an important role of the Per2 gene in maintenance of normal cardiovascular functions.

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Relation between circadian patterns in levels of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men

Cited by 80 publications

References 59 publications

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women

Diurnal, Seasonal, and Blood-Processing Patterns in Levels of Circulating Fibrinogen, Fibrin D-Dimer, C-Reactive Protein, Tissue Plasminogen Activator, and von Willebrand Factor in a 45-Year-Old Population

Mutation of the Circadian Clock Gene Per2 Alters Vascular Endothelial Function

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