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Interindividual variations in drug m...

Munoz, Claudio Enrique.

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Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions./
Author:	Munoz, Claudio Enrique.
Description:	111 p.
Notes:	Adviser: J. David Spence.
Contained By:	Dissertation Abstracts International63-05B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NQ68098
ISBN:	0612680983

Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions.
Munoz, Claudio Enrique.

Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions. - 111 p.

Adviser: J. David Spence.

Thesis (Ph.D.)--The University of Western Ontario (Canada), 2002.

Significant pharmacokinetic drug interactions can occur between propafenone and CYP3A4 inhibitors depending on CYP2D6 activity. These studies suggest the importance of knowing the phenotype/genotype of patients in order to prevent drug interactions.

ISBN: 0612680983Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions.
LDR:03584nam 2200301 a 45 001 932677
005 20110505
008 110505s2002 eng d
020 $a 0612680983
035 $a (UnM)AAINQ68098
035 $a AAINQ68098
040 $a UnM $c UnM
100 1 $a Munoz, Claudio Enrique. $3 1256420
245 1 0 $a Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions.
300 $a 111 p.
500 $a Adviser: J. David Spence.
500 $a Source: Dissertation Abstracts International, Volume: 63-05, Section: B, page: 2331.
502 $a Thesis (Ph.D.)--The University of Western Ontario (Canada), 2002.
520 $a Significant pharmacokinetic drug interactions can occur between propafenone and CYP3A4 inhibitors depending on CYP2D6 activity. These studies suggest the importance of knowing the phenotype/genotype of patients in order to prevent drug interactions.
520 $a Interindividual differences in drug metabolism may be an important factor determining drug interactions. One goal of this thesis was to compare the effects of the CYP3A4 inhibitors, ketoconazole (KTC), erythromycin (ERM) and grapefruit juice (GFJ), on the pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, propafenone. It is normally extensively metabolized by cytochrome P450 2136 (CYP2D6), an enzyme that shows genetic polymorphism, and moderately metabolized by CYP3A4 and CYPIA2. The first study assessed the interaction in 12 subjects with different CYP2D6 activity. Subjects with high CYP2D6 activity (n = 9) had low plasma peak propafenone concentration (Cmax, 0.09 ± 0.03 μg/mL, mean ± SD) and area under the curve (AUC, 0.28 ± 0.15 μg.h/mL, mean ± SD) with water (control). These parameters were not altered by any CYP3A4 inhibitor. Subjects with low CYP2D6 activity (n = 3) had high propafenone Cmax (0.82 ± 0.24) and AUC (7.59 ± 4.87) with water. These parameters were further increased by KTC (1.36 ± 0.07, 13.10 ± 4.91; p < 0.01), ERM (1.24 ± 0.54, 10.09 ± 4.13, p < 0.05) and GFJ (1.06 ± 0.36, 10.13 ± 3.87, p < 0.05) suggesting that the interaction was relevant to individuals with low CYP2D6 activity.
520 $a In a follow-up study, 114 subjects were screened for CYP2D6 activity and six CYP2D6 poor metabolizers (PM) were tested. Propafenone Cmax and AUC with water (0.96 ± 0.30; 11.01 ± 3.22) were increased by KTC (1.90 ± 0.60; 23.60 ± 6.70, p < 0.001), ERM (1.30 ± 0.30; 16.50 ± 5.10, p < 0.05) and GFJ (1.50 ± 0.60; 16.10 ± 4.50, p < 0.05). There were no significant changes in electrocardiogram recordings in CYP2D6 PM with CYP3A4 inhibitors.
520 $a A third study compared the effects of 4 week administration of GFJ or orange juice (OJ, control) on the activity of warfarin (International Normalized Ratio, INR) in 23 patients undergoing stable anticoagulation therapy. Warfarin is primarily metabolized by CYP2C9, which exhibits genetic polymorphism, and by several other CYP450 enzymes including CYP3A4. There was no difference in mean warfarin dose/INR ratio between treatments assessed weekly. No individual had consistently lower warfarin dose/INR ratio with GFJ compared to OJ.
590 $a School code: 0784.
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
710 2 0 $a The University of Western Ontario (Canada). $3 1017622
773 0 $t Dissertation Abstracts International $g 63-05B.
790 $a 0784
790 1 0 $a Spence, J. David, $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NQ68098