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Effect of chronic renal failure on c...

Rege, Bhaskar Mahesh.

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Effect of chronic renal failure on cytochrome P450 catalytic activities.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Effect of chronic renal failure on cytochrome P450 catalytic activities./
Author:	Rege, Bhaskar Mahesh.
Description:	259 p.
Notes:	Director: Mohamadi A. Sarkar.
Contained By:	Dissertation Abstracts International64-02B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3082012
ISBN:	9780496298631

Effect of chronic renal failure on cytochrome P450 catalytic activities.
Rege, Bhaskar Mahesh.

Effect of chronic renal failure on cytochrome P450 catalytic activities. - 259 p.

Director: Mohamadi A. Sarkar.

Thesis (Ph.D.)--Virginia Commonwealth University, 2003.

Purpose. The pharmacokinetics of drugs predominantly undergoing renal elimination can be significantly perturbed in chronic renal failure (CRF). In addition, there have been studies indicating significantly altered metabolic clearances, of drugs that are primarily eliminated by the liver in CRF patients. The objective of the present study was to evaluate possible mechanisms to explain the altered metabolic clearance of drugs in renal failure.

ISBN: 9780496298631Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Effect of chronic renal failure on cytochrome P450 catalytic activities.
LDR:04171nam 2200313 a 45 001 946985
005 20110523
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020 $a 9780496298631
035 $a (UMI)AAI3082012
035 $a AAI3082012
040 $a UMI $c UMI
100 1 $a Rege, Bhaskar Mahesh. $3 1270403
245 1 0 $a Effect of chronic renal failure on cytochrome P450 catalytic activities.
300 $a 259 p.
500 $a Director: Mohamadi A. Sarkar.
500 $a Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0656.
502 $a Thesis (Ph.D.)--Virginia Commonwealth University, 2003.
520 $a Purpose. The pharmacokinetics of drugs predominantly undergoing renal elimination can be significantly perturbed in chronic renal failure (CRF). In addition, there have been studies indicating significantly altered metabolic clearances, of drugs that are primarily eliminated by the liver in CRF patients. The objective of the present study was to evaluate possible mechanisms to explain the altered metabolic clearance of drugs in renal failure.
520 $a Methods. In-Vitro Studies: CRF was induced in male Sprague-Dawley rats (n = 7) by the 5/6th Nephrectomy method; control animals (C) (n = 12) underwent SHAM surgery of which n = 6 rats were pair-fed (CPF) along with CRF rats. The progression of CRF was monitored by measuring serum creatinine (Scr) and blood urea nitrogen (BUN) every two weeks. On day 36 after the surgery, animals were sacrificed, livers were isolated and microsomes were prepared by differential centrifugation method. CYP450 catalytic activities were measured through O-demethylation of dextromethorphan (CYP2D), N-demethylation of dextromethorphan (CYP3A) and O-deethylation of 7-ethoxyresorufin (CYP1A2). Michaelis Menten parameters were determined under optimal incubation conditions. The regulation of CYP450 enzymes was assessed by measuring mRNA expression by RT-PCR and protein levels by Western Blot analysis. In-Vivo Studies: CRF was induced in Sprague-Dawley rats (n = 6) by 5/6th Nephrectomy method. The other groups of animals, C (n = 5) and CPF (n = 5) underwent SHAM surgery. Hepatic and intestinal CYP3A activity was measured by administering oral and intravenous (iv) midazolam (10 mg/kg). Non-compartmental and compartmental pharmacokinetic analyses of concentration-time profiles for midazolam were performed using WINNONLIN (v. 3.1) software.
520 $a Results. In both, in-vitro as well as in-vivo studies, renal failure was evident in CRF group by 2--3 fold increases in S cr and BUN levels as compared to CPF and C group. The in-vitro studies showed a significant reduction in CYP3A (41.8 +/- 20%, p < 0.01) activity, which was accompanied by decrease in CYP3A2 m-RNA and protein levels (normalized to beta-actin) (p < 0.05) in CRF compared to CPF animals. CRF did not appear to have any effect on CYP1A2, and CYP2D activity, expression or protein levels. The in-vivo studies showed 3-fold reduction in apparent clearance (CLt) with corresponding increase in dose normalized AUC values in CRF as compared to CPF group after oral administration. In addition, there was 3 fold increase in bioavailability of midazolam in CRF as compared to CPF group. The AUC and Clearance values after IV administration were similar between the three groups.
520 $a Conclusions. Based on our results, it appears that, CRF causes isoform-specific effect resulting in significant reduction in CYP3A activity due to downregulation of CYP3A2 isozyme. Inhibition of hepatic and intestinal metabolism could result in clinically significant exposure of drugs; suggesting that the dosage adjustments may be necessary even for highly hepatically metabolized drugs in CRF patients. This research emphasizes the need to evaluate pharmacokinetics of new drugs that are predominantly eliminated by hepatic metabolism in CRF patients.
590 $a School code: 2383.
650 4 $a Health Sciences, Pharmacology. $3 1017717
650 4 $a Health Sciences, Pharmacy. $3 1017737
690 $a 0419
690 $a 0572
710 2 $a Virginia Commonwealth University. $3 1018010
773 0 $t Dissertation Abstracts International $g 64-02B.
790 $a 2383
790 1 0 $a Sarkar, Mohamadi A., $e advisor
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3082012