The Metabolism Of Chloroquine Phosphate By Rat Liver Cell Fractions
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Date
1979-06
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Publisher
University of Ghana
Abstract
1. The metabolisn of chloroquine phosphate by the various
subcellular fractions of the rat liver honnogenate has been
studied.
(a) Both the mitochondrial and soluble fractions were
found to contain enzyme systems that degraded
chloroquine to varying degrees.
(b) The maximum activity of chloroquine degradation
was however found in the microsomal fraction,
2. In vitro studies on the metabolisij of (ring-3-^C) chloroquine
led to the conclusion that the microsomal subcellular fraction was
capable of breaking chloroquine down to a minimum of eight metabolites
in which the 4-aminoquinoline nucleus remained intact.
3. A number of 4-aminoquinoline derivatives, including the
4'-hydroxy, the 4'-aldehyde, the primary amine (SN 13617) derivatives
of chloroquine have been successfully synthesized and
characterized,
4. Using the synthesized derivatives of chloroquine as
chromatographic standards, four of the eight metabolites of
chloroquine (see ' 2 * above) were identified as the primary amine
derivative (SN 13617), the 4'-hydroxy and the 4'-aldehyde derivatives
and 7 -chloro-4-aminoquinoline. 5. Based on in vitro studies on the metabolism of
both chloroquine and the synthesized derivatives by
the hepatic microsomal fraction of rat, it has been
tentatively suggested that the metabcLlic degradation
of chloroquine proceeds by the formation of the
following metabolit.££.• in the order:
i) The hydroxychloroquine, HCQ (ie. the analogue
of chloroquine in which a hydroxyl group has
been substituted in the 2-position of N-ethyl
groups).
ii) The secondary amine derivative (SN 13616);
iii) The primary amine derivative (SN 13617);
iv) The 4'-aldehyde derivative, which is largely
converted into the 4'-hydroxy derivative.
6 . An alternative pathway for the secondary amine
derivative ('SN 13616) has also been proposed. Through
this pathway, chloroquine may be converted through
SN 13616 and an unidentified intermediate V, to a
final product 4-amino-7-chloroquinoline. It has also
been demonstrated that in presence of SKF 525A, the
metabolism of chloroquine is apparently activated
through the latter alternative pathway.
7. Evidence is also presented to show that the
proposed pathway for chloroquine metabolism might
be common to both the rat and man.
Description
Thesis(M.Phil)-University of Ghana, 1979