Item – Theses Canada

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OCLC number
46498419
Author
Luo, Hong,1959-
Title
Investigations in human of the N-glucuronidation of drugs with an aliphatic tertiary amine group.
Degree
Ph. D. -- University of Saskatchewan, 1994
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, 1995.
Description
3 microfiches.
Notes
Includes bibliographical references.
Abstract
The major objectives of the present work were to develop a general approach to organic synthetic procedures for N$\sp+$-glucuronides and to investigate the scope of N$\sp+$-glucuronidation for antipsychotic, antidepressant and H$\sb1$ antihistamine drugs. The first general approach to organic synthesis of quaternary ammonium-linked glucuronide metabolites of compounds with an aliphatic tertiary amine group was developed. The key step involved quaternization of the compound with methyl (2,3,4-tri-O-acetyl-$\alpha$- scD-glucopyranosyl bromide) uronate and sodium bicarbonate in a two-phase system of water and an organic solvent. This approach yielded N$\sp+$-glucuronides of a structurally diverse range of compounds with functional groups such as alcohol, alkene, ether, sulfide, sulfone and sulfoxide. Physical data such as HPLC retention times, diagnostic fast atom bombardment (FAB) and electrospray (ES) mass spectra, and $\sp1$H NMR spectra were obtained that have been utilized in the characterization of these compounds in samples isolated from biological media. In addition, the heteroaromatic type N$\sp+$-glucuronide of nicotine and the N-glucuronide of the secondary amine type drug desipramine were synthesized by a modification of this procedure. Ten antipsychotics, five antidepressants and nine H$\sb1$ antihistamines from various structural classes of these drugs were investigated as to the presence of the N$\sp+$-glucuronide metabolite in the urine and feces of healthy volunteers and/or patients who in each case received the appropriate drug orally under an approved protocol. Of the 24 drugs examined, an N$\sp+$-glucuronide metabolite was identified in human urine for 15 of them. Only in the cases of imipramine and tripelennamine was such a metabolite previously reported. The present study implies that the formation of such metabolites in humans may be far more frequent than is indicated by the previous literature. For all five antidepressants (clomipramine, doxepin, imipramine, trazodone and trimipramine)--eight of nine H$\sb1$ antihistamines (chlorpheniramine, cyclizine, diphenhydramine, doxylamine, pheniramine, promethazine, pyrilamine and tripelennamine, but not terfanadine), but only two of the 10 antipsychotic drugs (clozapine and loxapine, but not chlorpromazine, fluphenazine, haloperidol, mesoridazine, sulforidazine, thioridazine, thiothixene and trifluoperazine)--studied, the N$\sp+$-glucuronidation pathway was observed in each of the subjects examined. Therefore, these data indicate that N$\sp+$-glucuronidation is a more general phenomenon in the metabolism of antidepressant and H$\sb1$ antihistamine drugs than antipsychotic drugs in humans. N$\sp+$-glucuronidation is a major route of metabolism in humans in the cases of cyclizine and doxepin. Also, on average more than 1% of the administered drug was excreted in the urine as the N$\sp+$-glucuronide in the cases of clozapine, diphenhydramine, loxapine, pheniramine and tripelennamine. In the case of doxepin, which has Z/E isomers, the Z/E ratio of doxepin N$\sp+$-glucuronide in the urine of patients was similar to that of the commercial formulation of doxepin administered. This indicates that such biotransformation is non-stereoselective. The N$\sp+$-glucuronide metabolite of cyclizine was detected in the feces of four of five orientals but none of five caucasians orally dosed with the drug. Further studies to delineate the reason(s) for this observed interethnic difference are warranted. (Abstract shortened by UMI.)
ISBN
0612001911
9780612001916