Defense Date

1983

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Robert V. Blanke

Second Advisor

Nedathur Narasimhachari

Abstract

An HPLC prodecure was developed for the simultaneous measurement of imipramine (IMP), desipramine (DMI), desmethyl desipramine (DMD), 2-hydroxyimipramine (2HI) and 2-hydroxydesipramine (2HD) in human, rat and rabbit blood and brain specimens. The HPLC results were validated by comparison to an established GC-MS method.

DMD is a minor metabolite of IMP and DMD in humans. 2HI is a minor metabolite of IMP in most humans. 2HD reaches appreciable concentrations in blood in humans treated with DMI and IMP. Plasma and RBC concentrations of IMP and DMI were compared to improvement in depression in patients treated with IMP. No good correlation was found. Plasma and RBC concentrations of DMI were compared to improvement in depression in patients treated with DMI. Plasma concentrations (r = -0.750, p < .01) and RBC concentrations (r = -0.693, p < .01) correlated with improvement in depression. As plasma DMI increased past 400 ng/ml, the degree of improvement declined.

In autopsy specimens from an IMP overdose, IMP, DMI, DMD, 2HI and 2HD were all measured in whole blood and brain. In autopsy specimens from b/0 DMI overdoses, DMI, DMD and 2HD were all measured in whole blood and brain. The brain to blood ratios in all cases for IMP and DMI were significantly higher than the brain to blood ratio of 2HD, the most polar metabolite. This finding indicates that 2HD has restricted entry into the brain compared to IMP and DMI. The distribution of 2HD between plasma and brain was studied in rats. The mean brain to plasma ratio for DMI was 5.87 and for 2HD it was 0.067. Therefore, in rats 2HD has limited access into brain from blood compared to DMI.

In rat studies, both plasma and RBC concentrations of DMI correlated well with brain DMI concentrations. In humans and rats, the plasma to RBC ratios for IMP and DMI are significantly different. IMP has greater affinity for plasma than RBCs. DMI is the reverse, having greater affinity for RBCs than plasma. As indicated, for DMI treated patients, plasma DMI concentrations correlated slightly better than RBC DMI concentrations to patient improvement in depression.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-7-2016

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