In the treatment of arrhythmias, amiodarone is a primary therapeutic agent. Cytochromes P450 (CYP) 1A1 and 1A2 facilitate biotransformation of amiodarone to the biologically active desethylamiodarone. Side effects have been reported during therapy and some are correlated with increased desethylamiodarone levels. Exposure to polycyclic aromatic hydrocarbons (PAH) like -naphthoflavone induces CYP1A1 and CYP1A2 and therefore can increase desethylamiodarone levels. Desethylamiodarone, however, was reported to inactivate human CYP1A1 and therefore can conceivably inhibit its CYP1A1-mediated formation. Our primary objective was to investigate the effect of -naphthoflavone on amiodarone disposition. Since rats were used, CYP isoenzymes involved in desethylamiodarone formation in human were compared to their rat counterparts. The effect of ketoconazole on desethylamiodarone formation, the inactivating potential of desethylamiodarone on CYP1A1 and the mechanism of -naphthoflavone-amiodarone interaction were assessed. Human CYP1A1 and rat CYP2D1 had the highest intrinsic clearance (Clint) for desethylamiodarone. Human and rat CYP1A2 had the lowest Clint. Ketoconazole (18.8 M) inhibited all isoforms except for rat CYP1A2; it potently inhibited human CYP1A1 and CYP3A4 and rat CYP2D2 and CYP1A1. After a single amiodarone dose was administered to control and -naphthoflavone pretreated rats, the plasma area under concentration-time curve (AUC) of desethylamiodarone increased. With multiple doses, amiodarone AUC(0-24h) decreased in -naphthoflavone plasma (30%), lung (35%), liver (48%), kidney (52%), heart (34%), and intestine (43%). Desethylamiodarone AUC(0-24h) increased in -naphthoflavone plasma (36%), lung (56%), liver (101%), kidney (65%), and heart (73%). Desethylamiodarone caused no inactivation of CYP1A1 when preincubations were diluted and nicotinamide adenine dinucleotide phosphate (NADPH) was added in the probe incubation samples. Evidence for reversible mixed-competitive inhibition was apparent. Addition and/or replenishment of NADPH were important factors in maintaining control activity. -naphthoflavone increased desethylamiodarone formation only in lung and kidney microsomes. Desethylamiodarone formation in liver, intestine and heart microsomes was not altered. Body-weight-normalized liver mass was significantly increased (27%) by -naphthoflavone. In conclusion, human CYP1A1 was more efficient in forming desethylamiodarone than rat isoenzyme. Exposure to PAH increased desethylamiodarone levels in vivo. Increased desethylamiodarone levels were partly caused by CYP1A1 induction, and by increased liver mass. Desethylamiodarone did not inactivate CYP1A1 activity. / Pharmaceutical sciences

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Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains xi, 145 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 134-142).

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A 47-year-old male had bilateral upper extremity thrombophlebitis after use of intravenous amiodarone for sustained ventricular tachycardia complicating myocardial infarction. Intravenous amiodarone has been widely used since it was introduced 20 years ago for severe intractable arrhythmias. Superficial thrombophlebitis was frequently noted in the early case reports when high-dose intravenous amiodarone was used. Superficial thrombophlebitis could extend hospitalization and become a significant source of distress to our patients. Some authors recommend insertion of a central line to administer intravenous amiodarone especially with expected extended use of therapy. The treating physician should be vigilant and switch from intravenous therapy to oral therapy as soon as the patient's condition stabilizes and oral therapy can be started.

Thèse de doctorat : Médecine. Biologie moléculaire : Université de Nantes : 2004. / Bibliogr. f. 168-189.

Amiodarone (AM) is a potent antidysrhythmic agent which can cause potentially life-threatening pulmonary fibrosis, and N-desethylamiodarone (DEA) is a metabolite of AM that may contribute to the toxicity of AM in vivo. Recent evidence has implicated the involvement of the renin-angiotensin system (RAS) in the initiation and progression of amiodarone-induced pulmonary toxicity. In cultured HPL1A human peripheral lung epithelial cells, we found AM to be converted to DEA minimally (< 2%) after 24 h of incubation, indicating that the HPL1A cell culture model can be used to study the effects of AM and DEA independently. Apoptotic cell death was assessed by annexin-V-FITC (ann-V) staining and by terminal deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphate nick-end labeling (TUNEL), while necrotic cell death was determined by propidium iodide (PI) staining. The percentage of PI positive cells increased over six-fold after 24 h treatment with 20 μM AM (80.8%) compared to control (12.0%), and doubled after 24 h treatment with 3.5 μM DEA (20.4%) compared to control (10.8%). The percentage of ann-V positive cells decreased from 8.26% (control) to 1.56% following 24 h treatment with 10 μM AM and more than doubled after 24 h incubation with 3.5 μM DEA (22.0%) compared to control (9.86%) (p<0.05). Treatment for 24 h with 5.0 μM DEA caused the percentage of TUNEL positive cells to increase from 4.21% (control) to 26.7% (p<0.05). Vitamin E (5 – 20 μM) did not protect against AM or DEA cytotoxicity, as determined by ann-V and PI dual staining. Angiotensin II (100 pM – 1 μM) alone or in combination with AM or DEA did not alter cytotoxicity. Furthermore, the angiotensin converting enzyme inhibitor captopril did not protect against AM or DEA cytotoxicity. In conclusion, in vitro, AM activates primarily necrotic pathways, whereas DEA activates both necrotic and apoptotic pathways, and the RAS does not seem to be involved in AM or DEA cytotoxicity in HPL1A cells. Multiple mechanisms may contribute to the initiation of lung damage observed clinically, due to actions of both AM and its metabolite DEA. Keywords: amiodarone, desethylamiodarone, vitamin E, renin-angiotensin system / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2009-11-26 13:57:09.65

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。