METABOLIC INTERACTION OF CINCHONA ALKAIDIES WITH MERIOXYPHENANDNE AND CHLORPROMAZINE : PHARMACCGENETIC SIUDIES IN MAN AND RAT
| dc.creator | Muralidharan, Gopal | |
| dc.date.accessioned | 2023-12-13T20:30:58Z | |
| dc.date.available | 2023-12-13T20:30:58Z | |
| dc.date.issued | 1991-02 | |
| dc.date.submitted | February 1991 | |
| dc.description.abstract | Genetic polymorphism in metabolism is exhibited by several drugs including debrisavine and methoxyphenamine which are metabolized by debrisoquine 4-hydroxylase (designated in human as cytochrome P450I1D6). In the c of methoxyphenamine, the poor netabolizer phenotype differs Liam the extensive metabolizer in that after an oral dose there is impainrent in the formation of only those primary oxi-dative metabolites of methoxyphenamine that are catalyzed by cyto-chrome P450I1D6, namely O-desrcethylnethoxyphenamine and 5-hydroxy- methoxyphenamine. However, such an impairment is not seen in the formation of N-desmethylmethoNophenamine, the other known primary metabolite of methoxyphenamine. A similar situation occurs on administration of methoxyphenamine to Lewis and Dark Agouti strains of rats, the purported extensive and poor netabolizer models, respec-tively, of human debrisoquine polymorphism. Various studies were conducted in humans and rats (Lewis and Dark Agouti strains) wherein the various phases methoxyphenamine was administered with and without prior treatment with quinidine (the most potent inhibitor known of the metabolic pathways of drugs that are catalyzed by cytochrame P450I1D6) or its diastereamer, quinine. Con-sistent to observations made using human liver preparations for drugs metabolized by cytochrome P45011D6, it was seen in vivo that quinidine was a potent inhibitor of the O-demethylation and 5-hydroxylation of methoxyphenamine in human, whereas quinine failed to inhibit these metabolic pathways. In rats, however, quinine was a far more potent inhibitor of these metabolic pathways than quinidine. Thus for the first time indication was obtained from in vivo studies that the iso-zymes catalyzing the metabolism of those drugs which co-segregate with debrisoquine polymorphism are different in human and rat. These studies provided further support for the use of methoxyphenamine as a phenotyping agent for drugs exhibiting 'debrisoquine type' metabolic polymorphism. Administration of the prototype phencthiazine antipsychotic agent chlorpromazine with and without prior quinidine treatment to humans helped to identify the involvement in part of cytochrcne P450I1D6 in its 7-hydroxylation. 'Ibis was confirmed by using methoxyphenamine as a phencstyping agent. Thus, a metabolic pathway of this class of drugs which exhibits polymorphism was identified for the first time. | |
| dc.identifier.uri | https://hdl.handle.net/10388/15348 | |
| dc.title | METABOLIC INTERACTION OF CINCHONA ALKAIDIES WITH MERIOXYPHENANDNE AND CHLORPROMAZINE : PHARMACCGENETIC SIUDIES IN MAN AND RAT | |
| dc.type.genre | Thesis | |
| thesis.degree.department | Pharmacy | |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |