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dc.creatorYan, Jing-Heen_US
dc.date.accessioned2004-10-21T00:22:10Zen_US
dc.date.accessioned2013-01-04T05:05:17Z
dc.date.available1999-01-01T08:00:00Zen_US
dc.date.available2013-01-04T05:05:17Z
dc.date.created1999-01en_US
dc.date.issued1999-01-01en_US
dc.date.submittedJanuary 1999en_US
dc.identifier.urihttp://hdl.handle.net/10388/etd-10212004-002210en_US
dc.description.abstractThe tricyclic antidepressant doxepin is marketed as a mixture of geometric isomers in a cis:trans ratio of 15:85. In most 'in vivo' and ' in vitro' tests, the cis-isomer is the more potent of the two geometric forms. Doxepin is metabolized to a variety of phase I and phase II metabolites, in which the N-desmethyl metabolite is thought to make an important contribution to therapeutic activity and it has been suggested that plasma concentrations of (cis plus trans) doxepin and (cis plus trans) desmethyldoxepin show better correlation with antidepressant activity than (cis plus trans) concentrations of the parent drug alone. In recent years, there have been a number of research papers published reporting that the ratio of cis(Z)- to trans(E)- desmethyldoxepin equals or surpasses unity in plasma or urine of patients or healthy volunteers after oral administration of doxepin, while this significant ratio distortion is not evident for the parent drug. Therefore, an investigation into the mechanism of this significant ratio distortion was warranted. The first pilot studies involved oral doses of doxepin in male volunteers (n = 4) and four animal species (dog, rabbit, guinea pig, and rat) in small groups (n = 4 or n = 3). Ratio distortion of desmethyldoxepin was found with varying degrees in cumulative 24 hour urine. A parallel study with three groups of male Lewis strain rats (n = 4) was carried out to investigate the effects of route of administration on the 24 hour urinary excretion of the isomers of doxepin and desmethyldoxepin. There was no significant effect of route on percentage Z-doxepin (p = 0.3262), but the effect of route on percentage desmethyidoxepin was highly significant (p = 0.0001). A cross-over study in a group of male Lewis strain rats (n = 8) was carried out, in which each animal received E-desmethyldoxepin, E-doxepin and doxepin by both intravenous and oral routes. 'In vitro' metabolic studies were performed with rat and human liver microsomes; experiments with rat GIT tissue homogenates; and enzyme inhibition studies with rat liver microsomes utilizing UGT inhibitors. The results from these studies indicated that: (i) Consistent with the ' in vivo' studies, there was no evidence of interconversion between isomers; (ii) increase in the percentage of Z-desmethydoxepin was a time dependent progressive process; (iii) the reason for the ratio distortion lay in more rapid metabolic elimination of the E-desmethyldoxepin; (iv) no trace of desmethyldoxepin was found in incubates of doxepin with rat GIT subcellular homogenates; and (v) the N-glucuronidation of desmethyldoxepin was very likely the stereoselective metabolic pathway responsible. The final part of the thesis describes cross-over, iv/oral stereoselective pharmacokinetic studies on doxepin and desmethyldoxepin in young male volunteers (n = 12) and beagle dogs (n = 6). (Abstract shortened by UMI.)en_US
dc.language.isoen_USen_US
dc.titleStereoselective metabolic and pharmacokinetic studies on antidepressant : doxepin and desmethyldoxepinen_US
thesis.degree.departmentPharmacyen_US
thesis.degree.disciplinePharmacyen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophy (Ph.D.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US
dc.contributor.committeeMemberMidha, Kamal K.en_US
dc.contributor.committeeMemberHawes, Edwarden_US


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