In vivo 4-hydroxylation of amphetamine in the rat

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Title In vivo 4-hydroxylation of amphetamine in the rat
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Law, Michael Yiu Lun.
Date 1994-08
Description The predominant pathway for amphetamine metabolism in the rat is 4-hydroxylation. Limited in vitro data on the inhibition of debrisoquine hydroxylation by amphetamine suggest cytochrome P-450 (P450) 2D1 has a role in this reaction. In a preliminary experiment in which Lewis rats were pretreated with the P450 2D inhibitor, quinidine, reduced excretion of 4'-hydroxyamphetamine in the urine was found. As amphetamine and its metabolites are primarily excreted in the urine, measurement of urinary 4'-hydroxyamphetamine and amphetamine is a reasonable approach to study amphetamine's in vivo metabolism. An HPLC-UV method was developed in order to quantify 4'-hydroxyamphetamine and amphetamine in rat urine samples. In the initial study using P450 2D1-deficient Dark Agouti (DA) rats, a decrease in the excretion of 4'-hydroxyamphetamine (expressed as percentage of administrated dose) was found in the DA male (7.1 ± 2.3) and DA female (10.0 ± 2.8), as compared to the Sprague Dawley (SD) male (67.9 ± 6.3) and SD female (53.0 ± 8.3) rats. P450 2D's involvement in amphetamine 4'-hydroxylation was also established by enzyme induction and inhibition studies in SD rats. In vivo induction of P450s by 3-methylcholanthrene, phenobarbital, isosafrole, ethanol, pregnenolone-16/alpha-carbonitrile, clofibrate, and di-(2-ethylhexyl) phthalate produced minimal, if any, increase in the urinary excretion of 4'-hydroxyamphetamine. However, in vivo inhibition of P450s resulted in reduced excretion of 4'-hydroxyamphetamine (expressed as percentage of controls) in SD male rats pretreated with: 1-aminobenzotriazole, 7.2 ± 2.2; quinidine, 17.3 ± 1.6; quinine, 30.1 ± 5.9; and primaquine, 17.6 ± 7.4%. Neither diallyl sulfide, a P450 2E inhibitor, nor troleandomycin, a P450 3A inhibitor, reduced 4'-hydroxyamphetamine excretion (81.9 ± 13.4 and 76.4 ± 16.2% of control, respectively). The reduction in the urinary excretion of 4'-hydroxyamphetamine in the rats correlated positively p = 0.80) with decreases in a microsomal P450 2D1-dependent monooxygenase activity in rats which received the same inhibition treatments. This correlation, together with the findings of decreased 4-hydroxylation of amphetamine in female DA rats and in rats where P450 2D1-dependent monooxygenase activities have been inhibited, has now provided 2 independent lines of evidence to link P450 2D to amphetamine 4-hydroxylation.
Type Text
Publisher University of Utah
Subject Metabolism; Hydrosylation
Subject MESH Amphetamines; Amphetamine-Related Disorders
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "In vivo 4-hydroxylation of amphetamine in the rat." Spencer S. Eccles Health Sciences Library. Print version of "In vivo 4-hydroxylation of amphetamine in the rat." available at J. Willard Marriott Library Special Collection. RM31.5 1994 .L39.
Rights Management © Michael Yiu Lun Law.
Format application/pdf
Format Medium application/pdf
Format Extent 1,909,569 bytes
Identifier undthes,4760
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship United States Publich Health Service Grant DA05102, the Center for Human Toxicology at the Universtiy of Utah, and the University of Utah's Research Committee.
Master File Extent 1,909,613 bytes
ARK ark:/87278/s6gt5pzv
Setname ir_etd
ID 190874
Reference URL https://collections.lib.utah.edu/ark:/87278/s6gt5pzv
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