| Summary: | The stereo-chemistry, structure activity relationships and the metabolism
of the anorectic drug, diethylpropion hydrochloride, have been reviewed
briefly, together with the analytical methods for the determination of
this drug and its metabolites in biological fluids. In addition, the
physico-chemical properties, mode of action, pharmacology and uses of the
metabolites have been presented.
A comprehensive review on general principles of salivary excretion of
drugs and their therapeutic drug monitoring in saliva with relevant
published data on saliva/plasma drug concentration relationships has been
outlined.
Sensitive and specific assay procedures, based on gas-liquid
chromatography for the identification, separation and determination of
diethylpropion and its two major metabolites i.e. ethylaminopropiophenone
(11) and diethylnorpseudoephedrine (IV) in aqueous and biological fluids,
have been developed. These methods were used to study the urinary
excreUon as well as saliva and plasma levels of the two major
metabolites and, where possible, the unchanged drug, in man.
Sustained release pellets with diffusion rate-controlled membranes were
employed to control the rate of input into the body by oral or rectal
route of administration. Urinary excretion data and plasma levels of
metabolites 11 and IV in volunteers, where the urine was controlled at an
acidic pH, were used for the evaluation of the bioavailabilities of
different dosage forms of diethylpropion hydrochloride. The
concentrations of metabolites 11 and IV were also measured in saliva and
in plasma after administration of the drug in different doses and dosage
forms: relationships between saliva and plasma concentrations (S/P) and
between urinary excretion rates and plasma concentrations (U/P) were
developed for each of the two metabolites during plateau levels after
oral administration of the sustained release pellets (Lot R 7773). The
potential use of salivary excretion of the metabolites as an index to
monitor their plasma levels and bioavailabilities, was examined.
The distinct advantage of using a subdivided controlled release system
(i. .e. sustained release pellets) to a single unit sustained release
tablet (erosion-core type) in relation to influence of the physical
presence of food on the rate and extent of absorption has been
demons t rated . It was found that the route of administration (oral or
rectal) did not significantly affect the bioavailability of the sustained
release pellets.
The study also involved the investigation of the release of the drug from
the pellets. Because the release control step was diffusion, no
significant influences on dissolution rates were observed with the use of
different dissolution test models and agitation intensities. The
influence of the concentration and composition (presence of cations viz.
Na+ and K+ i~r anions viz . phosphate and borate) of the dissolution
medium on the release of the drug from sustained release pellets, was
also studied. Any potential changes in the dissolution pattern on
storage of the pellets under different conditions (4°C, room temperature
and 37°C) ovrr, a period of at least one year, were investigated.
The in vitro and in vivo correlations of two lots of sustained release
pellets, each exhibiting different dissolution profiles, and administered
rectally and orally, were developed: the in vitro data on the free drug
were related to the sum of the urinary excretion data of metabolites II
and IV.
An attempt to use an empirical approach to predict urinary excretion rate
profiles of metabolite II after oral administration of the sustained
release pellets, was promising; the calculated profiles were reasonably
comparable with those of in vivo studies. However, the complete validity
of such equations needs further investigations. === Thesis (Ph.D.)-University of Durban-Westville, 1984.
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