The Influence of Hyperlipoproteinemia on in Vitro Distribution of Amiodarone and Desethylamiodarone in Human and Rat Plasma

Shayeganpour, Anooshirvan; Lee, Stephen D.; Brocks, Dion R.

doi:10.1007/s11095-006-9186-z

Cited by 23 publications

(20 citation statements)

References 19 publications

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“…The use of the Friedewald equation was unsuccessful in our rats probably due to a combination of the known higher-than-human concentrations of HDL-C in control rats, coupled with, in P407 treated rats, the very high concentrations of TG (39). Although it could not be estimated here, it is known through direct measure of cholesterol in the LDL fraction of plasma that LDL-C concentrations are very high at 36 h after P407 (37).…”

Section: Discussionmentioning

confidence: 87%

The Single Dose Poloxamer 407 Model of Hyperlipidemia; Systemic Effects on Lipids Assessed Using Pharmacokinetic Methods, and its Effects on Adipokines

Chaudhary

Brocks

2013

J Pharm Pharm Sci

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-Purpose:The induction of hyperlipidemia using poloxamer 407 (P407) is gaining use for studying the effect of the condition on drug pharmacokinetics. Although a single intraperitoneal dose of P407 causes a rapid onset of hyperlipidemia, the initial lipid concentrations are much higher than seen in humans. The hyperlipidemia is also reversible in nature. Here, pharmacokinetic methods were used to assess the P407 dose response on serum lipids, adipokines and cytokines. Methods: Single 0.5 and 1 g/kg doses of P407 were injected into rats followed by blood collection at various times for up to 12 d. Serum was assayed for lipids, selected adipokines and cytokines. Results: As expected, large increases in lipid levels were seen by 36 h after dosing. Using area under the concentration vs. time curve as a measure of systemic lipid exposure, P407 increased serum baseline corrected serum lipids in a nearly dose proportional fashion. The maximum increase in lipids was observed at ~36 h, with most lipids remaining elevated for up to ~180 h, although for the 1 g/kg dose triglyceride concentrations had still not quite returned to baseline by 12 days postdose. In addition to changes in lipids, P407 significantly increased serum leptin and decreased the serum adiponectin concentrations but did not affect cytokine levels. Conclusion: Depending on study aims, for the use of the model it may be beneficial to perform single-dose assessments at time points later than 36 h when the lipoprotein concentrations will be more similar to those seen in patient with hyperlipidemia.

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Section: Discussionmentioning

confidence: 87%

The Single Dose Poloxamer 407 Model of Hyperlipidemia; Systemic Effects on Lipids Assessed Using Pharmacokinetic Methods, and its Effects on Adipokines

Chaudhary

Brocks

2013

J Pharm Pharm Sci

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“…Therefore, it is anticipated that clomipramine binds to lipoproteins for its high lipophilicity, as described in the Introduction. Shayeganpou et al [29] . investigated the influence of lipoprotein on the distribution of amiodarone, which is used for the management of life‐threatening ventricular arrhythmias and has high binding characteristics to serum lipoproteins such as clomipramine in humans and P‐407‐induced hyperlipidaemic rat model plasma.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of clomipramine, an antidepressant, in poloxamer 407-induced hyperlipidaemic model rats

Kobuchi

Fukushima

Shibata

et al. 2011

Journal of Pharmacy and Pharmacology

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“…Therefore clearance (CL) and volume of distribution (V dss ) of DEA in both human and experimental animals have not been reported. This information would assist in understanding why the plasma concentrations of DEA, while measurable, are very low after administration of parent drug to rat, a species that was used to study the effects of hyperlipidemia on pharmacokinetics [10,18]. Therefore the main objective of the current study was to characterize the pharmacokinetic profile of DEA following oral and i.v.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

Shayeganpour

Hamdy

Brocks

2008

Biopharm & Drug Disp

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The pharmacokinetics of desethylamiodarone (DEA), the active metabolite of amiodarone (AM), were studied in the rat after administration of AM or preformed metabolite. Rats received 10 mg/kg of either intravenous or oral AM HCl or DEA base. Blood samples were obtained via a surgically implanted jugular vein cannula. Plasma concentrations were measured by a validated LC/MS method. In all AM treated rats, AM plasma concentrations greatly exceeded those of the formed DEA. The fraction of AM converted to DEA after i.v. administration was 14%. Amiodarone had a significantly lower (approximately 50%) clearance than DEA, although the volume of distribution and terminal phase half-life did not differ significantly. The hepatic extraction ratio of DEA was 0.48, similar to that of AM (0.51). Oral AM demonstrated higher plasma AUC (5.6 fold) and higher C(max) (6.1 fold) than oral DEA and oral bioavailability of AM (46%) was greater than DEA (17%). The estimated fraction of the oral dose of AM converted to DEA was 4.5 fold higher than after i.v. administration, suggesting first-pass formation of DEA from AM. Amiodarone and DEA differed in their pharmacokinetic characteristics mostly due to a higher CL of DEA. With oral dosing, AM appeared to undergo significant presystemic first-pass metabolism within the intestinal tract.

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The Influence of Hyperlipoproteinemia on in Vitro Distribution of Amiodarone and Desethylamiodarone in Human and Rat Plasma

Abstract: HL caused a major shift of AM and DEA to TRL fraction in both species. The findings were consistent with the higher AM concentrations previously noted in HL rats given the drug.

Cited by 23 publications

References 19 publications

The Single Dose Poloxamer 407 Model of Hyperlipidemia; Systemic Effects on Lipids Assessed Using Pharmacokinetic Methods, and its Effects on Adipokines

The Single Dose Poloxamer 407 Model of Hyperlipidemia; Systemic Effects on Lipids Assessed Using Pharmacokinetic Methods, and its Effects on Adipokines

Pharmacokinetics of clomipramine, an antidepressant, in poloxamer 407-induced hyperlipidaemic model rats

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

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