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Permanent link (DOI): https://doi.org/10.7939/R3H06S
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Polycyclic aromatic hydrocarbons and amiodarone pharmacokinetics Open Access
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University of Alberta
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta.
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Doctor of Philosophy
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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 β-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 β-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 β-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 μM) 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 β-naphthoflavone pretreated rats, the plasma area under concentration-time curve (AUC) of desethylamiodarone increased. With multiple doses, amiodarone AUC(0-24h) decreased in β-naphthoflavone plasma (30%), lung (35%), liver (48%), kidney (52%), heart (34%), and intestine (43%). Desethylamiodarone AUC(0-24h) increased in β-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.
Β-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 β-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.
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