A proposed mechanism for the adverse effects of acebutolol: CES2 and CYP2C19-mediated metabolism and antinuclear antibody production

Muta, Kyotaka; Fukami, Tatsuki; Nakajima, Miki

doi:10.1016/j.bcp.2015.09.016

Cited by 14 publications

(12 citation statements)

References 47 publications

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“…In general, the occurrence of ANA has a significantly closer association with female sex, older age, and the use of some classes of drugs [36][37][38][39]. In the present study, there was a slightly higher prevalence of ANA among female patients, although this difference was not significant.…”

Section: Discussioncontrasting

confidence: 69%

“…The RR is usually associated with chronic HCV infection treated with a combination of pegylated IFN and ribavirin [30][31][32][33][34][35][36][37][38][39][40][41][42][43]. However, data from other authors indicate that the ribavirin-dependent mechanism is not essential for the induction of these autoantibodies because this ANA pattern can also be detected in individuals with systemic lupus erythematosus [44], in individuals with HBV infection [41], and in clinically healthy individuals [45].…”

Section: Discussionmentioning

confidence: 99%

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High prevalence of antinuclear antibodies in patients with chronic hepatitis C virus infection

et al. 2022

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Background Hepatitis C virus (HCV) infection is a serious public health concern due to its high prevalence and mortality rate. In chronic infection, HCV may induce autoimmune responses through the production of autoantibodies, including antinuclear antibodies (ANA). Methods We assessed the presence of ANA by indirect immunofluorescence using HEp-2 cells in 89 patients with chronic hepatitis C. We also collected data on epidemiological variables; clinical characteristics; and biochemical, hematological, molecular, and histopathological information from the patients to assess the impact of the presence of ANA in those patients. Results The prevalence of ANA in the patients was 20.2%, which was significantly higher than that found in healthy controls (2%). However, there was no association of this marker with epidemiological, clinical-laboratory, molecular or histopathological characteristics of hepatitis C, although a slightly higher prevalence of ANA was detected in women and in patients infected with subgenotype 1a. In a specific analysis, chronic HCV patients with the “rods and rings” cytoplasmic pattern had higher degrees of hepatic fibrosis than did ANA-negative patients. Conclusions The results confirm a greater predisposition to the presence of ANA in patients with HCV, which may be associated with a worse prognosis, especially in the presence of the “rods and rings” cytoplasmic pattern.

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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

High prevalence of antinuclear antibodies in patients with chronic hepatitis C virus infection

et al. 2022

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“…Acebutolol is metabolised in the liver to give hepatoxic (active) metabolites such as diacetolol, hydroxylamine and 'auto-oxidised' metabolites, which are responsible for toxicity [82]. Hydrolysis forms an arylamine, and the CYP450 oxidation of arylamine induces toxicity [82].…”

Section: Drug Metabolism Pathwaysmentioning

confidence: 99%

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

et al. 2020

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Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t½), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short- (<10 min) and longer-circulation (>2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability.

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“…Carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC) play major roles in the hydrolysis of drugs. For example, CES1 catalyzes the hydrolysis of temocapril (an anti-hypertensive drug) and oseltamivir (an anti-influenza drug) (Takai et al, 1997;Shi et al, 2006), CES2 catalyzes the hydrolysis of irinotecan (an anticancer drug) and acebutolol (an anti-hypertensive and anti-arrhythmic drug) (Sanghani et al, 2004;Muta et al, 2015), and AADAC catalyzes the hydrolysis of rifampicin (antibiotics) and eslicarbazepine acetate (an anti-epileptic drug) (Nakajima et al, 2011;Hirosawa et al, 2021). CES1 is predominantly expressed in the liver, whereas CES2 and AADAC are expressed in the small intestine as well as the liver (Watanabe et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Drug-Drug Interactions via Inhibition of Hydrolases by Orlistat, an Anti-Obesity Drug

2023

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Drug-drug interactions (DDI) have a significant impact on drug efficacy and safety. It has been reported that orlistat, an anti-obesity drug, inhibits the hydrolysis of p-nitrophenol acetate, a common substrate of the major drug-metabolizing hydrolases, carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC), in vitro. The aim of this study was to examine whether orlistat affects the pharmacokinetics of drug(s) metabolized by hydrolases in vivo, after evaluating its inhibitory potencies against CES1, CES2, and AADAC in vitro.Orlistat potently inhibited the hydrolysis of acebutolol, a specific substrate of CES2, in a non-competitive manner (K i = 2.95 ± 0.16 nM), whereas it slightly inhibited the hydrolysis of temocapril and eslicarbazepine acetate, specific substrates of CES1 and AADAC, respectively (IC 50 > 100 nM). The in vivo DDI potential was elucidated using mice, in which orlistat showed strong inhibition against acebutolol hydrolase activities in the liver and intestinal microsomes, similar to humans. The AUC of acebutolol was increased by 43%, whereas the AUC of acetolol, a hydrolyzed metabolite of acebutolol, was decreased by 47% by co-administration of orlistat. The ratio of the K i value to the maximum unbound plasma concentration of orlistat (< 0.012) is lower than the risk criteria for DDI in the liver defined by the FDA guideline (> 0.02), whereas the ratio of the K i value to the estimated intestinal luminal concentration (3.3 × 10 5 ) is considerably higher than the risk criteria in the intestine (> 10). Therefore, this suggests that orlistat causes DDI by inhibiting hydrolases in the intestine.

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A proposed mechanism for the adverse effects of acebutolol: CES2 and CYP2C19-mediated metabolism and antinuclear antibody production

Cited by 14 publications

References 47 publications

High prevalence of antinuclear antibodies in patients with chronic hepatitis C virus infection

High prevalence of antinuclear antibodies in patients with chronic hepatitis C virus infection

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

Evaluation of Drug-Drug Interactions via Inhibition of Hydrolases by Orlistat, an Anti-Obesity Drug

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