Acebutolol is a β1-selective adrenergic receptor antagonist with moderate membrane-stabilizing activity and intrinsic sympathomimetic activity; accordingly, the drug is indicated in hypertension, angina pectoris, and arrhythmia. However, acebutolol's beta-blocking properties also extend the QRS and QTc intervals, and may predispose the patient to ventricular tachydysrhythmia. Here, we report autopsy and toxicological findings on a fatal case of acebutolol self-poisoning in a 70-year-old woman. Toxicological analyses of post-mortem samples (using a liquid chromatography high-resolution mass spectrometry (LC-HR-MS) method) highlighted high concentrations of acebutolol and its metabolite diacetolol in femoral blood (92.8 mg/L and 21.2 mg/L, respectively) and other matrices (cardiac blood, urine, bile, and gastric contents). A molecular networking approach provided useful information on acebutolol's metabolism and revealed the existence of an unknown phase II metabolite of acebutolol. Molecular networking also facilitated visualization of the complex LC-HR-MS/MS datasets and the sample-to-sample comparisons that confirmed massive acebutolol intoxication by ingestion.

01 Dec 2015·Biochemical PharmacologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Muta, Kyotaka ; Nakajima, Miki ; Fukami, Tatsuki

Acebutolol, a β-adrenergic receptor-blocker, occasionally causes drug-induced lupus erythematosus (DILE). Acebutolol is mainly metabolized to diacetolol. Because metabolic activation has been considered to be related to acebutolol-induced toxicity, we sought to identify the enzymes that are responsible for acebutolol metabolism and investigate their involvement in acebutolol-induced toxicity. By using human liver microsomes (HLM) or intestinal microsomes and recombinant enzymes, we found that diacetolol was produced via hydrolysis by carboxylesterase 2 (CES2) and subsequent acetylation by N-acetyltransferase 2 (NAT2). When acetolol, a hydrolytic metabolite of acebutolol, was incubated with HLM and an NADPH-generating system, a metabolite conjugated with N-acetylcystein was generated. This metabolite was found to be formed by CYP2C19 based on studies with a panel of recombinant cytochrome P450 enzymes and an inhibition study using HLM with tranylcypromine, a CYP2C19 inhibitor. Because antinuclear antibody (ANA) production is associated with DILE, we investigated whether ANA was detected in plasma from mice treated with acebutolol. Administration of acebutolol (100mg/kg, p.o.) to female C57BL/6 mice for 30 days resulted in ANA production in plasma in seven of thirteen mice. The number of mice that showed ANA production was larger in mice co-treated with pregnenolone 16α-carbonitrile, an inducer of P450s, whereas it was lower in mice co-treated with tri-o-tolylphosphate or 1-aminobenzotriazole, which are inhibitors of esterases or P450s, respectively. These results suggested that the hydrolysis and oxidation of acebutolol was associated with ANA production. In summary, this study demonstrated that metabolic activation may be a causal factor of adverse reactions of acebutolol.

12 Apr 2011·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Displacement of [3H]dihydroalprenolol binding from rat heart and lung by acebutolol, diacetolol and D-diacetolol

Q3 · MEDICINE

Article

Author: Pong, S F ; Tinkham, C L

Dihydroalprenolol-³H displacement studies in rat heart and lung homogenates confirmed the cardioselectivity and β₁-adrenoceptor antagonist properties of acebutolol (I; R = Pr) [37517-30-9] and diacetolol (I; R = Me) [22568-64-5].The contention is supported that diacetolol may contribute significantly to the pharmacol. activity of oral acebutolol in man.

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