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Protein binding and renal eliminatio...

Chun, Amy W.

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Protein binding and renal elimination characterization of aristolochic acids.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Protein binding and renal elimination characterization of aristolochic acids./
作者:	Chun, Amy W.
面頁冊數:	91 p.
附註:	Adviser: David R. Taft.
Contained By:	Masters Abstracts International46-02.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=1449020
ISBN:	9780549277804

Protein binding and renal elimination characterization of aristolochic acids.
Chun, Amy W.

Protein binding and renal elimination characterization of aristolochic acids. - 91 p.

Adviser: David R. Taft.

Thesis (M.S.)--Long Island University, The Brooklyn Center, 2007.

The principal focus of this research was to determine the extent of the protein binding of aristolochic acids (AA), and to utilize that data in estimating clearance values and understanding the net mechanisms of AA excretion. Excretion studies were performed in the presence of a known transport inhibitor (probenecid) in order to better understand the mechanisms through which AA's and their metabolites are transported. The main AA compounds investigated in this research were aristolochic acid I (AAI) and aristolochic acid II (AAII), as well as the main metabolite aristolochic acid-Ia (AA-Ia).

ISBN: 9780549277804Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Protein binding and renal elimination characterization of aristolochic acids.
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100 1 $a Chun, Amy W. $3 1267770
245 1 0 $a Protein binding and renal elimination characterization of aristolochic acids.
300 $a 91 p.
500 $a Adviser: David R. Taft.
500 $a Source: Masters Abstracts International, Volume: 46-02, page: 0937.
502 $a Thesis (M.S.)--Long Island University, The Brooklyn Center, 2007.
520 $a The principal focus of this research was to determine the extent of the protein binding of aristolochic acids (AA), and to utilize that data in estimating clearance values and understanding the net mechanisms of AA excretion. Excretion studies were performed in the presence of a known transport inhibitor (probenecid) in order to better understand the mechanisms through which AA's and their metabolites are transported. The main AA compounds investigated in this research were aristolochic acid I (AAI) and aristolochic acid II (AAII), as well as the main metabolite aristolochic acid-Ia (AA-Ia).
520 $a Protein binding assessments were completed by using equilibrium dialysis at the following concentrations: 50, 25 and 10 AM of AA. The determinations were made by studying the AA's alone and in the presence of probenecid. The extent of protein binding was determined by quantitating the unbound fractions and total concentrations using an HPLC method. In order to achieve separation between AA and probenecid, both AAI and AAII analysis required different mobile phases. The analysis showed that the compounds are highly protein bound at the concentrations studied. At the lowest concentration tested, the AAI and AAII were 98.1 and 99.5% bound respectively.
520 $a Isolated perfused rat kidney (IPK) experiments were carried out at a target concentration of 50 muM for AAI, and 5 muM for AAII and AA-Ia. All studies were conducted with the addition of probenecid (1mM) 50 minutes after AA dosing. Sample analysis was performed by HPLC utilizing a gradient method (total runtime of 85 minutes per sample). Samples containing AAI required the use of a Waters Bondapak C18 column in order to obtain adequate separation between AAI and the probenecid. AAII and AA-Ia samples were analyzed using a Waters Xterra C18 column. The results show that AAI exhibited an excretion ratio favoring net re-absorption, while AAII and AA-Ia show evidence of a net secretion mechanism.
520 $a In addition, the metabolite mAA-Ia (labeled mAA-Ia to differentiate) generated from studies with AAI, was identified in the samples. mAA-Ia was quantitated and evaluated by the same methods and calculations. Using an unbound fraction approximation of 0.02 (98% bound), the excretion ratio for mAA-Ia was calculated and exhibits elimination favoring secretion. In these experiments, mAA-Ia showed signs of inhibition by the probenecid. The renal excretion of all other compounds was unaffected by probenecid. Prior to the probenecid addition, mAA-Ia demonstrated net renal secretion. Following the probenecid administration, the clearance decreased 5-fold, and the net mechanism of excretion was reabsorption. Based on this observation, mAA-Ia is transported through the organic anion transporter in the kidney. However, when dosed directly into the IPK, AA-Ia does not seem to have the same mechanisms as the metabolized mAA-Ia.
520 $a The mechanism(s) by which AA's exert carcinogenic and nephrotoxic effects in the kidney remain elusive. By discovering what these mechanisms are, we hope to further our understanding of what causes nephropathy in humans, which may in turn lead to more effective treatments or prevention. The studies conducted in this thesis dissertation supported ongoing research to address this important issue.
590 $a School code: 0198.
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
710 2 $a Long Island University, The Brooklyn Center. $3 1017735
773 0 $t Masters Abstracts International $g 46-02.
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790 1 0 $a Taft, David R., $e advisor
791 $a M.S.
792 $a 2007
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