Abstract 329: Mechanism by Which Anacetrapib Lowers Plasma Lipoprotein (a) Concentration

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Tiffany A Thomas ◽  
Haihong Zhou ◽  
Thomas Roddy ◽  
Stephen Previs ◽  
Michael Lassman ◽  
...  
Keyword(s):  
Plasma Lipoprotein ◽  
Entire Group ◽  
Fixed Sequence ◽  
Lipoprotein A ◽  
Synthetic Rate ◽  
Period 2 ◽  
Catabolic Rate ◽  
Fractional Synthetic Rate ◽  
Cetp Inhibitor ◽  
Sequence Study

Objective: Anacetrapib, a CETP inhibitor, was previously shown to decrease plasma lipoprotein (a) [Lp(a)] levels by 35-40% in subjects also taking a statin. Thus, anacetrapib is an efficacious Lp(a)-lowering agent. The goal of this study was to define the mechanism by which anacetrapib lowers plasma Lp(a) levels. Methods: 39 moderately hyperlipidemic volunteers were enrolled in a fixed-sequence study, in which 75% were on atorvastatin 20mg/day, plus placebo for four weeks (period 1), and then atorvastatin plus anacetrapib (100 mg/day) for 8 weeks (period 2). The other 25% of the subjects received double placebo for four weeks, and then placebo plus anacetrapib for 8 weeks. Turnover studies using D3-leucine were performed at the end of each period. The present analysis utilized samples from a subset of subjects (n=12) who had plasma Lp(a) levels greater than 10 nM at the end of period 1 and had a greater than 10% reduction in Lp(a) by the end of period 2. The fractional synthetic rate (FSR:equal to fractional catabolic rate at steady state) of mature Lp(a), isolated from a D:1.019-1.21 g/ml density interval, was determined from the enrichment of a leucine-containing peptide specific to apo(a). The production rate (PR) of mature Lp(a) was calculated from the FSR and the Lp(a) pool size. To date, we have calculated the FSR and PR in 4 participants. Results: Baseline Lp(a) mean levels were 45.7 ± 6.3nM in the entire group and 56.5 ± 33.6nM in the 12 qualifying subjects. Anacetrapib lowered Lp(a) by 43 ± 22% in the 12 subjects and 21 ±12% in the 4 subjects with turnover data. In these 4 subjects, the reduction in mature Lp(a) was associated with a 24% reduction in FSR and a 41% reduction in PR. Lp(a) kinetics analyses of the remaining 8 subjects are in progress. Conclusion: These preliminary results suggest that anacetrapib decreases Lp(a) levels by significantly decreasing the production of mature Lp(a). Additional analyses are planned to determine if the reduced production of Lp(a) results from decreased entry of Lp(a) into plasma or reduced conversion of a precursor form to the mature Lp(a).

An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15060-e15060
Author(s):  
Christopher G. C. A. Jackson ◽  
Noelyn Anne Hung ◽  
David Cutler ◽  
Douglas Kramer ◽  
Jay Zhi ◽  
...  
Keyword(s):  
Treatment Period ◽  
Dabigatran Etexilate ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Healthy Male ◽  
Open Label ◽  
Fixed Sequence ◽  
Once Daily ◽  
Period 2 ◽  
Sequence Study

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m2 with a significantly lowered Cmax and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and Cmax values for dabigatran were both increased ̃ 95% without changing t½ when dabigatran etexilate was administered 1 hour post the 3rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or Cmax were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and Cmax were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for Cmax). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in < 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.

α2-Antiplasmin: Functional Characterization and Metabolism in a Heterozygote Deficient Patient

1986 ◽  
Vol 55 (03) ◽  
pp. 375-378 ◽  
Author(s):  
E A R Knot ◽  
J W ten Cate ◽  
R J Lamping ◽  
Liem Kian Gie
Keyword(s):  
Half Life ◽  
Functional Characterization ◽  
Bleeding Tendency ◽  
Normal Range ◽  
Crossed Immunoelectrophoresis ◽  
Synthetic Rate ◽  
Catabolic Rate ◽  
Deficient Patient ◽  
Antigen Activity ◽  
Bleeding History

SummaryAn 81-year-old male with a mild life-long bleeding history and an α2-antiplasmin (α2-AP) plasma level of 55% biological activity and 41% antigen activity (normal range 80-140%) was studied. The ratio of plasminogen binding (PB): non-plasminogen binding (NPB) α2-AP assayed by modified crossed immunoelectrophoresis (CIE) was 7.3/2.7 (controls 6.3 ± 0.49 SD/3.7 ± 0.49 SD). The patient’s α2-AP showed decreased affinity for fibrin, i. e. 8.3% versus 32.4% of normal control α2-AP associated with fibrin during clotting of plasma. A metabolic study performed with human purified 125I-α2-AP(PB/NPB 7.7/2.3) showed a plasma radioactivity disappearance half-life of 72.9 h (n 60.1 ± 5.3 h) with a normal fractional catabolic rate and a reduced absolute catabolic (synthetic) rate of 0.70 mg/kg/day (n 2.10 ± 0.60 mg/kg/day). The exchange between the central and third compartment was increased. The increased α2-AP PB form and the increased plasma radioactivity disappearance half-life are suggestive of a slower conversion of the PB form into the NPB form and/or slower degradation of the PB form. The bleeding tendency in this patient could be explained by decreased synthesis of α2-AP and decreased binding to fibrin.

Differential effects of obesity with and without hyperinsulinemia on plasma lipoprotein(a) concentrations in men

Metabolism ◽  
2001 ◽  
Vol 50 (2) ◽  
pp. 178-183 ◽  
Author(s):  
Carlos Posadas-Romero ◽  
Antonio Hernández-Ono ◽  
José Zamora-González ◽  
Guillermo Cardoso-Saldaña ◽  
Liria Yamamoto-Kimura ◽  
...  
Keyword(s):  
Plasma Lipoprotein ◽  
Differential Effects ◽  
Lipoprotein A

scholarly journals Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients

2010 ◽  
Vol 55 (1) ◽  
pp. 326-330 ◽  
Author(s):  
José Moltó ◽  
Marta Valle ◽  
Cristina Miranda ◽  
Samandhy Cedeño ◽  
Eugenia Negredo ◽  
...  
Keyword(s):  
High Performance ◽  
Geometric Mean ◽  
Echinacea Purpurea ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Root Extract ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Sequence Study

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome.

1998 ◽  
Vol 9 (8) ◽  
pp. 1474-1481
Author(s):  
M G De Sain-Van Der Velden ◽  
D J Reijngoud ◽  
G A Kaysen ◽  
M M Gadellaa ◽  
H Voorbij ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Synthesis Rate ◽  
Fractional Synthesis Rate ◽  
Lipoprotein A ◽  
Control Subjects ◽  
Apolipoprotein A ◽  
Catabolic Rate ◽  
Fractional Synthesis ◽  
The Mean

In patients with the nephrotic syndrome, markedly increased levels of lipoprotein(a) (Lp(a)) concentration have been frequently reported, and it has been suggested that this may contribute to the increased cardiovascular risk in these patients. The mechanism, however, is not clear. In the present study, in vivo fractional synthesis rate of Lp(a) was measured using incorporation of the stable isotope 13C valine. Under steady-state conditions, fractional synthesis rate equals fractional catabolic rate (FCR). FCR of Lp(a) was estimated in five patients with the nephrotic syndrome and compared with five control subjects. The mean plasma Lp(a) concentration in the patients (1749+/-612 mg/L) was higher than in control subjects (553+/-96 mg/L). Two patients were heterozygous for apolipoprotein(a) (range, 19 to 30 kringle IV domains), whereas all control subjects were each homozygous with regard to apolipoprotein(a) phenotype (range, 18 to 28 kringle IV domains). The FCR of Lp(a) was comparable between control subjects (0.072+/-0.032 pools/d) and patients (0.064+/-0.029 pools/d) despite the wide variance in plasma concentration. This suggests that differences in Lp(a) levels are caused by differences in synthesis rate. Indeed, the absolute synthetic rate of Lp(a) correlated directly with plasma Lp(a) concentration (P < 0.0001) in all subjects. The present results demonstrate that increased synthesis, rather than decreased catabolism, causes elevated plasma Lp(a) concentrations in the nephrotic syndrome.

Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis

2001 ◽  
Vol 91 (3) ◽  
pp. 1041-1047 ◽  
Author(s):  
G. Parise ◽  
S. Mihic ◽  
D. MacLennan ◽  
K. E. Yarasheski ◽  
M. A. Tarnopolsky
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Fat Free Mass ◽  
Whole Body ◽  
Synthetic Rate ◽  
Fractional Synthetic Rate ◽  
Before And After ◽  
Total Creatine ◽  
Plasma Leucine

Creatine monohydrate (CrM) supplementation during resistance exercise training results in a greater increase in strength and fat-free mass than placebo. Whether this is solely due to an increase in intracellular water or whether there may be alterations in protein turnover is not clear at this point. We examined the effects of CrM supplementation on indexes of protein metabolism in young healthy men ( n = 13) and women ( n = 14). Subjects were randomly allocated to CrM (20 g/day for 5 days followed by 5 g/day for 3–4 days) or placebo (glucose polymers) and tested before and after the supplementation period under rigorous dietary and exercise controls. Muscle phosphocreatine, creatine, and total creatine were measured before and after supplementation. A primed-continuous intravenous infusion of l-[1-13C]leucine and mass spectrometry were used to measure mixed-muscle protein fractional synthetic rate and indexes of whole body leucine metabolism (nonoxidative leucine disposal), leucine oxidation, and plasma leucine rate of appearance. CrM supplementation increased muscle total creatine (+13.1%, P < 0.05) with a trend toward an increase in phosphocreatine (+8.8%, P = 0.09). CrM supplementation did not increase muscle fractional synthetic rate but reduced leucine oxidation (−19.6%) and plasma leucine rate of appearance (−7.5%, P < 0.05) in men, but not in women. CrM did not increase total body mass or fat-free mass. We conclude that short-term CrM supplementation may have anticatabolic actions in some proteins (in men), but CrM does not increase whole body or mixed-muscle protein synthesis.

Plasma Lipoprotein(a) [LP(a)] Concentrations and Apoprotein(a) [APO(a)] Isoforms in Chronic Renal Disease

1997 ◽  
Vol 93 (s37) ◽  
pp. 13P-13P
Author(s):  
DA Reaveley ◽  
M Misra ◽  
N Al-Khalaf ◽  
E Brown ◽  
J Alaghband-Zadeh
Keyword(s):  
Renal Disease ◽  
Chronic Renal Disease ◽  
Plasma Lipoprotein ◽  
Lipoprotein A

scholarly journals Regulation of low-density-lipoprotein metabolism in the rat

1986 ◽  
Vol 234 (2) ◽  
pp. 493-496 ◽  
Author(s):  
S Bhattacharya ◽  
S Balasubramaniam ◽  
L A Simons
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hormonal Control ◽  
Low Density ◽  
Experimental Conditions ◽  
Synthetic Rate ◽  
Catabolic Rate ◽  
Intermediate Density

The mechanism of regulation of plasma low-density-lipoprotein (LDL) metabolism in the rat was studied under a number of experimental conditions. LDL clearance and uptake in the liver was measured after intravenous pulse injection of [14C]sucrose-labelled LDL alone or in combination with reductively methylated [3H]sucrose-labelled LDL. Hyperthyroid rats showed a significant increase in fractional catabolic rate (FCR) and the proportion of LDL degraded in the liver, whereas the synthetic rate of LDL increased by 50%. Receptor-mediated clearance increased 2-fold. Hypothyroid rats showed a significant increase in LDL concentration. The FCR and proportion of LDL degraded in the liver were decreased significantly. Receptor-mediated clearance was also reduced. Cholesterol feeding increased chylomicron, very-low-density-and intermediate-density-lipoprotein cholesterol concentrations, but there was no change in the LDL concentration, FCR or the synthetic rate of LDL. Cholestyramine feeding did not induce changes in the kinetic parameters. These results indicate that, in the rat, the hepatic LDL-receptor pathway is under hormonal control, whereas cholesterol and cholestyramine feeding have no demonstrated effect on LDL metabolism.

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