Disposition pharmacokinetics of bezafibrate in man

Abshagen, U.; Bablok, W; Koch, Klaus; Lång, Pernilla; Schmidt, H. A. E.; Senn, Martin; Stork, H.

doi:10.1007/bf00644963

Cited by 55 publications

(29 citation statements)

References 9 publications

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“…39 μg·h/mL) [54,55]. On the other hand, these parameters in rats after the single low-dose administration were relatively similar to those in healthy volunteers (21 μg/mL and 107 μg·h/mL, respectively).…”

Section: Discussionsupporting

confidence: 56%

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

Nakajima

Tanaka

Sugiyama

et al. 2008

Biochemical Pharmacology

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Section: Discussionsupporting

confidence: 56%

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

Nakajima

Tanaka

Sugiyama

et al. 2008

Biochemical Pharmacology

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“…Human pharmacokinetic data that correspond to our mouse data from 10 mg/kg/day bezafibrate treatment have been reported (Ali et al, 2002;Kajosaari et al, 2004) but differ somewhat from those of an earlier report (Abshagen et al, 1979). This disagreement might have derived from differences in determination procedure of serum bezafibrate concentrations (high-performance liquid chromatography versus gas chromatography) and racial and/or anthropometric differences of the subjects.…”

Section: Downloaded Fromsupporting

confidence: 63%

“…1 (n ϭ 3 at each time point). The pharmacokinetic data for bezafibrate-treated humans were reported by three groups: Kajosaari et al (2004) determined C max and AUC from 0 to 8 h in 12 healthy male volunteers after 5-day oral administration of a 400-mg slow-release tablet; Abshagen et al (1979) calculated those from 0 to 10 h in 10 healthy male subjects after a single intake of 300-mg tablets; and Ali et al (2002) measured those from 0 to 9 h in 14 healthy male volunteers after single oral administration of a 200-mg tablet. 19 Ϯ 2 2 0 Ϯ 2 2 2 Ϯ 3 1 6 Ϯ 2 1 7 Ϯ 2 1 8 Ϯ 2 Aspartate aminotransferase (IU/l) 61 Ϯ 7 6 2 Ϯ 5 7 7 Ϯ 11 71 Ϯ 6 7 0 Ϯ 10 72 Ϯ 9 Alanine aminotransferase (IU/l) 15 Ϯ 2 1 5 Ϯ 1 1 8 Ϯ 2 1 3 Ϯ 2 1 4 Ϯ 2 1 5 Ϯ 1 Liver data TG (mg/g liver) 16 Ϯ 3 8 Ϯ 2* 6 Ϯ 2* 39 Ϯ 6 2 2 Ϯ 9* 60 Ϯ 14 FFA (Eq/g liver) 15 Ϯ 1 1 4 Ϯ 2 1 7 Ϯ 2 2 3 Ϯ 4 2 0 Ϯ 4 3 3 Ϯ 8 * P Ͻ 0.05, between treated and untreated mice of the same genotype.…”

Section: Methodsmentioning

confidence: 99%

Bezafibrate at Clinically Relevant Doses Decreases Serum/Liver Triglycerides via Down-Regulation of Sterol Regulatory Element-Binding Protein-1c in Mice: A Novel Peroxisome Proliferator-Activated Receptor α-Independent Mechanism

Nakajima¹,

Tanaka²,

Kanbe³

et al. 2009

Mol Pharmacol

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The triglyceride-lowering effect of bezafibrate in humans has been attributed to peroxisome proliferator-activated receptor (PPAR) ␣ activation based on results from rodent studies. However, the bezafibrate dosages used in conventional rodent experiments are typically higher than those in clinical use (Ն50 versus Յ10 mg/kg/day), and thus it remains unclear whether such data can be translated to humans. Furthermore, because bezafibrate is a pan-PPAR activator, the actual contribution of PPAR␣ to its triglyceride-lowering properties remains undetermined. To address these issues, bezafibrate at clinically relevant doses (10 mg/kg/day; low) was administered to wild-type and Ppara-null mice, and its effects were compared with those from conventionally used doses (100 mg/kg/day; high). Pharmacokinetic analyses showed that maximum plasma concentration and area under the concentration-time curve in bezafibrate-treated mice were similar to those in humans at low doses, but not at high doses. Low-dose bezafibrate decreased serum/liver triglycerides in a PPAR␣-independent manner by attenuation of hepatic lipogenesis and triglyceride secretion. It is noteworthy that instead of PPAR activation, down-regulation of sterol regulatory element-binding protein (SREBP)-1c was observed in mice undergoing low-dose treatment. High-dose bezafibrate decreased serum/liver triglycerides by enhancement of hepatic fatty acid uptake and ␤-oxidation via PPAR␣ activation, as expected. In conclusion, clinically relevant doses of bezafibrate exert a triglyceride-lowering effect by suppression of the SREBP-1c-regulated pathway in mice and not by PPAR␣ activation. Our results may provide novel information about the pharmacological mechanism of bezafibrate action and new insights into the treatment of disorders involving SREBP-1c.Bezafibrate and other fibrate drugs are clinically used as hypolipidemic agents to preferentially lower serum triglyceride (TG) levels. Several large-scale clinical trials have demonstrated a relationship between the TG-lowering effect of fibrates and a reduction in the risk of cardiovascular events in patients with dyslipidemia, type 2 diabetes mellitus, and metabolic syndrome (BIP Study Group, 2000;Keech et al., 2005;Tenenbaum et al., 2005). The mechanisms accounting for the hypolipidemic effect of fibrates in humans are explained mainly as an increase in the lipolysis of TG-rich lipoproteins, such as very-low-density lipoprotein (VLDL),

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“…The erythrocyte membrane is permeable to bezafibrate. Although the results described herein are encouraging from a clinical viewpoint, it remains to be seen whether a bezafibrate dose (450 mg-600 mg/d) as used in the therapy of hyperlipidemia patients (24) can build a concentration of this drug in erythrocytes sufficient to benefit the oxygen transport capacity. It is important to realize that the oral dose ofbezafibrate employed in the therapy of hyperlipidemia patients will yield a plasma concentration at least an order of magnitude below that employed in the in vitro work presented in this paper.…”

Section: Discussionmentioning

confidence: 88%

Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

Sugihara¹,

Imamura²,

Nagafuchi³

et al. 1985

J. Clin. Invest.

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We encountered an abnormal hemoglobin (Rahere), with a threonine residue replacing the ,682 (EF6) lysine residue at the binding site of 2,3-diphosphoglycerate, which was responsible for overt erythrocytosis in two individuals of a Japanese family. Hemoglobin Rahere shows a lower oxygen affinity on the binding of 2,3-diphosphoglycerate or chloride ions than hemoglobin A. Although a decrease in the positive charge density at the binding sites of 2,3-diphosphoglycerate in hemoglobin Rahere apparently shifts the allosteric equilibrium toward the low affinity state, it greatly diminishes the cofactor effects by anions. The oxygen affinity of the patient's erythrocytes is substantially lowered by the presence of bezafibrate, which combines with sites different from those of 2,3-diphosphoglycerate in either hemoglobin Rahere or hemoglobin A.

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Disposition pharmacokinetics of bezafibrate in man

Cited by 55 publications

References 9 publications

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

Bezafibrate at Clinically Relevant Doses Decreases Serum/Liver Triglycerides via Down-Regulation of Sterol Regulatory Element-Binding Protein-1c in Mice: A Novel Peroxisome Proliferator-Activated Receptor α-Independent Mechanism

Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

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