The Metabolic Profile of Azimilide in Man: In Vivo and in Vitro Evaluations

Riley, P.A.; Figary, P.C.; Entwisle, John; Roe, Amy L.; Thompson, Gary A.; Ohashi, Rikiya; Ohashi, Nobuyuki; Moorehead, Thomas J.

doi:10.1002/jps.20429

Cited by 10 publications

(12 citation statements)

References 16 publications

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“…Azimilide metabolism is mediated by CYP1A1 ($25%) and CYP3A4 ($15%). 7 Since CYP1A1 is primary located extrahepatically, 26 changes in azimilide clearance would not be anticipated in hepatic dysfunction. Conversely, CYP3A4 is the major hepatic enzyme involved in the metabolism of drugs, [27][28][29] whose activity is decreased by $30-50% in subjects with hepatic impairment.…”

Section: Discussionmentioning

confidence: 99%

“…Formation of F-1292 via cleavage accounts for $35% of azimilide's total clearance, with cytochrome P450 3A4/5 and cytochrome P450 1A1 accounting for $15 and 25% of azimilide's total clearance, respectively. 7 Azimilide's major metabolite in plasma is a carboxylic acid moiety (F-1292), which does not possess cardiovascular activity. 8,9 Minor metabolites also found in plasma include desmethyl azimilide (NE-10171 base), azimilide N-oxide (NE-10835), and azimilide carboxylate (NE-11178).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Mild and Moderate Hepatic Impairment on Azimilide Pharmacokinetics Following Single Dose Oral Administration

Corey¹,

Agnew²,

King³

et al. 2004

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Mild and Moderate Hepatic Impairment on Azimilide Pharmacokinetics Following Single Dose Oral Administration

Corey¹,

Agnew²,

King³

et al. 2004

Journal of Pharmaceutical Sciences

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“…On the basis of the conceptual framework discussed in Theoretical Considerations of Determining In Vivo Metabolite Exposure, this was ascribed to either a low CL f and/ or a high CL m for the metabolite. For instance, low circulating concentrations of N-desalkyl metabolites of azimilide (Riley et al, 2005), elzasonan (Kamel et al, 2010), imatinib (Gschwind et al, 2005), itraconazole (Isoherranen et al, 2004), olanzapine (Kassahun et al, 1997), propafenone (Kroemer et al, 1989), and repaglinide (van Heiningen et al, 1999) can be attributed to the relatively minor contribution of N-dealkylation to the overall clearance of these drugs. On the other hand, low circulating concentrations of mchlorophenylpiperazine (Fig.…”

Section: Secondary or Primary Amines As Metabolitesmentioning

confidence: 99%

Which Metabolites Circulate?

2013

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Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (f m ). Our analysis suggests that f m is the major determinant of total drug M/P ratio for amine, alcohol, N-and S-oxide, and carboxylic acid metabolites. Passage from the hepatocyte to systemic circulation does not appear to be limiting owing to the vast majority of metabolites formed being relatively lipid permeable. In some cases, active transport plays an important role in this process (e.g., carboxylic acid metabolites). Differences in total parent drug clearance and metabolite clearance are attenuated by the reduction in lipophilicity introduced by the metabolic step and resultant compensatory changes in unbound clearance and protein binding. A small subclass of these drugs (e.g., terfenadine) is unintentional prodrugs with very high parent drug clearance, resulting in very high M/P ratios. In contrast, arenol metabolites show a more complex relationship with f m due largely to the new metabolic routes (conjugation) available to the metabolite compared with the parent drug molecule. For these metabolites, a more thorough understanding of the elimination clearance of the metabolite is critical to discern the likelihood of whether the phenol will constitute a major circulating metabolite.

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“…1), with renal clearance accounting for only approximately 10% of total clearance. Cleavage of the isocyanide bond leading to the formation of the carboxylic acid F‐1292 [4], the major metabolite in plasma, accounts for about 35% of the total clearance of azimilide. Minor metabolites in plasma are desmethylazimilide, azimilide N‐oxide and azimilide carboxylate.…”

Section: Introductionmentioning

confidence: 99%

“…Since the plasma concentrations of the desmethyl and N‐oxide metabolites are only 10% of those of azimilide, they do not contribute measurably to antiarrthymic activity in vivo [6]. Metabolism by CYP3A4/5 and CYP1A1 accounts for 15% and 25%, respectively, of the total clearance of azimilide [4].…”

Section: Introductionmentioning

confidence: 99%

Influence of ketoconazole on azimilide pharmacokinetics in healthy subjects

Mouelhi

Worley

Kuzmak

et al. 2004

Brit J Clinical Pharma

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AimTo assess the influence of ketoconazole on azimilide pharmacokinetics. MethodsA two-period randomized crossover study was conducted in healthy male and female subjects (19-45 years). Placebo or 200 mg ketoconazole were administered orally every 24 h for 29 days. On day 8, a single oral dose of 125 mg azimilide dihydrochloride was coadministered following an overnight fast. Blood samples were obtained prior to and for 22 days following azimilide dihydrochloride administration. The plasma protein binding of azimilide was also assessed at 6 h after dosing. ResultsFollowing ketoconazole administration, a 16% increase in azimilide AUC (90% confidence interval (CI) 112%, 120%), a 12% increase in C max (95% CI 107%, 116%), a 13% increase in t 1/2,z (95% CI 107%, 120%) and a 14% decrease in CL o (95% CI 82%, 90%) were observed. ConclusionsThe changes in azimilide pharmacokinetics following ketoconazole treatment are not clinically important since the 90% CI for the AUC fell within the prespecified range of 80-125%. Thus, no clinically important drug interactions are expected when azimilide dihydrochloride is coadministered with CYP3A4 inhibitors.

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The Metabolic Profile of Azimilide in Man: In Vivo and in Vitro Evaluations

Cited by 10 publications

References 16 publications

Effect of Mild and Moderate Hepatic Impairment on Azimilide Pharmacokinetics Following Single Dose Oral Administration

Effect of Mild and Moderate Hepatic Impairment on Azimilide Pharmacokinetics Following Single Dose Oral Administration

Which Metabolites Circulate?

Influence of ketoconazole on azimilide pharmacokinetics in healthy subjects

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