Monitoring hepatic cholesterol 7α-hydroxylase activity by assay of the stable bile acid intermediate 7α-hydroxy-4-cholesten-3-one in peripheral blood

Gälman, Cecilia; Arvidsson, Ingela; Angelin, Bo; Rudling, Mats

doi:10.1194/jlr.d200043-jlr200

Cited by 175 publications

(159 citation statements)

References 40 publications

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“…The two clinically desired results were a lowering of serum LDL cholesterol levels, and based on measurements of established bio-markers for bile-acid and cholesterol synthesis (18,19), an increase in bile acid synthesis in the absence of an effect on cholesterol synthesis. In the 2-week study, KB2115 lowered serum cholesterol levels to a maximal level of 40% reduction.…”

Section: Discussionmentioning

confidence: 99%

“…Serum lipids including cholesterol (total, LDL, HDL), triglycerides, free fatty acids, apoA-I, apoB, and lipoprotein a were measured in fasting samples. Also changes in bile acid and cholesterol synthesis rates were assessed by measurements of C4/ cholesterol and lathosterol/cholesterol as described (18,19).…”

Section: Methodsmentioning

confidence: 99%

“…For this purpose, serum levels of lathosterol were determined as a marker for total body cholesterol synthesis (18) and of 7␣-hydroxy-4-cholesten-3-one (C4) as a marker for hepatic bile acid synthesis (18,19). As shown in Fig.…”

Section: Pharmacodynamic Effects On Thyroid Hormone Homeostasis and Lmentioning

confidence: 99%

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The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans

Berkenstam

Kristensen

Mellström

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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173

131

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Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115; (3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in hu-mans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans

Berkenstam

Kristensen

Mellström

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

173

131

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“…Thus, elobixibat decreases the plasma LDL‐C level. Concurrently, elobixibat increases the level of the intermediate product of BA synthesis: plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), which is a surrogate of the hepatic BA synthesis rate 14, 15. Another factor likely to increase BA synthesis is food intake, which may influence the pharmacological action of elobixibat.…”

Section: Introductionmentioning

confidence: 99%

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

Kumagai

Aoki

Sasaki

et al. 2018

Brit J Clinical Pharma

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AimsElobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.MethodsThis study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.ResultsFood consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple‐dose test, elobixibat reduced low‐density lipoprotein cholesterol and increased C4 whilst unaltering high‐density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.ConclusionsElobixibat should be taken before breakfast. Once‐daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.

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“…Aunque se debe estandarizar el momento de la toma de la prueba ya que presenta variabilidad diurna (37).…”

Section: Diagnósticounclassified

Diarrea pos colecistectomía, enfoque diagnóstico y terapéutico

Jaramillo¹,

S²,

Regino³

2017

Rev. Med.

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RESUMENLa colelitiasis es una enfermedad muy prevalente en la población general. El tratamiento de la colelitiasis, cuando se torna sintomática, es fundamentalmente quirúrgico. Una de sus complicaciones es la diarrea pos-colecistectomía que se define como la presencia de 3 o más deposiciones diarreicas por día por más de cuatro semanas en pacientes con el antecedente de colecistectomía, en ausencia de otra causa que explique la sintomatología. Debido a la incidencia reportada en la literatura alrededor del 15%, esta revisión presenta la epidemiologia, fisiopatología, diagnóstico, clasificación y tratamiento de esta patología. Adicionalmente se plantea una nueva clasificación de la patología que se correlacione con la fisiopatología.

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Monitoring hepatic cholesterol 7α-hydroxylase activity by assay of the stable bile acid intermediate 7α-hydroxy-4-cholesten-3-one in peripheral blood

Cited by 175 publications

References 40 publications

The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans

The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

Diarrea pos colecistectomía, enfoque diagnóstico y terapéutico

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