Pharmacokinetics of Guanabenz in Patients with Impaired Liver Function

Lasseter, Kenneth C.; Shapse, Deborah; Pascucci, Virginia L.; Chiang, Soong T.

doi:10.1097/00005344-198400065-00008

Cited by 6 publications

(4 citation statements)

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“…The molecular weight of Ga is 291.1 and its KD value against HELZ2 is 2.3 × 10 –9 M. Ga is an α2-adrenergic receptor agonist with a Ki value of 7 × 10 –9 M 24 and exerts its effects at the central and peripheral levels to decrease blood pressure 24 . The half-life of Ga is 4.3 h, and its estimated efficacy is 12 h. Approximately 75% of orally administered Ga is absorbed by the gastrointestinal tract, and nearly all of Ga is metabolized in the liver.…”

Section: Resultsmentioning

confidence: 99%

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity

Yoshino

Iwasaki

Matsumoto

et al. 2020

Sci Rep

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nonalcoholic fatty liver disease (nAfLD) is characterized by excessive accumulation of hepatic triglycerides (tG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for nAfLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse nAfLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed nAfLD development and body weight (BW) gain in obese mice. A highthroughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients. NAFLD commonly develops with obesity and is the hepatic component of metabolic syndrome, and its prevalence is increasing worldwide 1. NAFLD encompasses a wide spectrum of chronic pathological liver conditions ranging from simple hepatosteatosis to NASH and cirrhosis, and occurs in approximately 25% of adults globally 2. The prevalence of NAFLD is more than 50% among patients with T2DM 3 , and these patients are at an increased risk of liver-related mortality and cardiovascular disease 2, 3. The liver consists of various cell types with hepatocytes being the main parenchymal cells, in which lipid droplets, mainly TG, accumulate, and an excessive TG content in hepatocytes is a hallmark of NAFLD 4,5. An increased liver TG content is a predictor of hepatic insulin resistance, which causes hyperglycemia, independently of visceral adipocyte volumes or body mass index in individuals with obesity 4,5. Insulin resistance is associated with lipid deposition in the peripheral metabolic organs such as the liver, WAT, BAT and skeletal muscle. Moreover, hepatic steatosis in almost all cases has been shown to precede the development of insulin resistance in other peripheral metabolic organs 4-6. Decreasing excessive lipid levels in the liver was reported to attenuate insulin resistance, thereby ameliorating hyperglycemia in subjects with T2DM and/or NAFLD 7-9. A prolonged high blood level of insulin, attributed to hepatic insulin resistance, contributes in the progression of NAFLD to liver fibrosis, NASH and possibly hepatocellular carcinoma 1,10,11. Effective pharmacological treatments are urgently needed to treat N...

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Section: Resultsmentioning

confidence: 99%

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity

Yoshino

Iwasaki

Matsumoto

et al. 2020

Sci Rep

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“…The onset of the Guanabenz pharmacological action occurs in 1-2 h and persists for approximately 8 up to 12 h, while the plasma peak concentration is achieved within 2-5 h after oral administration (Meacham et al 1981). It is quickly absorbed into the gastrointestinal tract, subjected to extensive hepatic first-pass metabolism and eliminated in the urine within the first 24 h mainly as the inactive metabolite (E)-p-hydroxyguanabenz (Lasseter et al 1984). Less than 1% of the dose is excreted as an unchanged drug.…”

Section: Introductionmentioning

confidence: 99%

Guanabenz—an old drug with a potential to decrease obesity

Kotańska

Knutelska

Nicosia

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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The aim of this study was to determine, in the diet-induced obesity model in rats, the potential of Guanabenz to reduce body weight and ameliorate some metabolic disturbances. Obesity was induced in rats by a high-fat diet. After 10 weeks, rats were treated intraperitoneally with Guanabenz at the two doses: 2 or 5 mg/kg b.w./day, once daily for 25 days. The spontaneous activity of rats was measured for 24 h on the 1st and 24th day of the Guanabenz treatment with a special radio-frequency identification system. Gastric emptying was measured in intragastric phenol red-treated mice by measuring the color of the stomach homogenate 30 min after phenol red administration. Intraperitoneal administration of Guanabenz for 25 days to obese rats resulted in a significant decrease in body weight compared to the baseline values (about 11% at a dose of 5 mg/ kg). Both body weight and the amount of adipose tissue in the groups receiving Guanabenz decreased to the levels observed in the control rats fed only standard feed. The anorectic effect occurred in parallel with a reduction in plasma triglyceride levels. We also confirmed the beneficial effect of Guanabenz on plasma glucose level. The present study demonstrates that the administration of Guanabenz strongly inhibits gastric emptying (about 80% at a dose of 5 mg/kg). Guanabenz can successfully and simultaneously attenuate all the disorders and risk factors of metabolic syndrome: hypertension, hyperglycemia, obesity, and dyslipidemia. However, the exact cellular mechanisms of its action require further research.

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“…Guanabenz is another direct central α 2 ‐agonist, which is predominantly eliminated via hepatic biotransformation 28,29 . Thus, unlike clonidine, dose adjustment is not required in patients with renal failure but required in those with chronic liver diseases.…”

Section: Guanabenzmentioning

confidence: 99%

Central Sympatholytic Drugs

Vongpatanasin

Kario

Atlas

et al. 2011

The Journal of Clinical Hypertension

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J Clin Hypertens (Greenwich). 2011;13:658–661. ©2011 Wiley Periodicals, Inc. Key Points Central sympatholytic drugs reduce blood pressure mainly by stimulating central α2‐adrenergic receptors in the brainstem centers, thereby reducing sympathetic nerve activity and neuronal release of norepinephrine to the heart and peripheral circulation. This class of drugs, however, is currently used mainly as fourth‐line (or beyond) drug therapy for hypertension because of side effects of drowsiness, fatigue, and dry mouth. Rebound hypertension is also another major concern in certain drugs with a short half‐life, particularly in patients who are nonadherent to the regimen. Therefore, their use on a “PRN” basis for treatment of blood pressure surge in the absence of symptoms or acute target complications should also be avoided.

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Pharmacokinetics of Guanabenz in Patients with Impaired Liver Function

Cited by 6 publications

References 0 publications

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity

Guanabenz—an old drug with a potential to decrease obesity

Central Sympatholytic Drugs

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