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Abstract
The effects of daily oral administration of a high dose of 10 mg norethisterone acetate
(NET-Ac.)/kg/day over 14 weeks on serum lipid and lipoprotein parameters as well as
on blood coagulation were investigated in female monkeys (M. fascicularis). Measurements
of lipids and lipoprotein cholesterol were performed in weeks —5 and — 1 before treatment
and in weeks 4, 8 and 12 after treatment. In addition, various blood coagulation and
fibrinolytic parameters were determined in weeks 11–14 after treatment with NET-Ac.
Furthermore, the serum levels of norethisterone (NET) were determined in order to
monitor the real systemic compound exposure and revealed that Cmax and AUC (0–3 h) values reached for norethisterone in this experiment in monkeys were
about 25 times higher than those obtained after an oral contraceptive dose of NET-Ac.
in women.
The results of lipid and lipoprotein cholesterol determinations showed decreases in
serum total lipids, phospholipids, triglycerides and total cholesterol associated
with similar decreases in HDL-, LDL- and VLDL-cholesterol fractions after NET-Ac.-treatment
in monkeys. These effects were observed from week 4 onwards and maintained their magnitude
up to week 12 after treatment. Since both HDL- and LDL-cholesterol fractions decreased,
the HDL/LDL-ratio remained almost unchanged. Thus, the results obtained in this study
after high-dose treatment with NET-Ac. in monkeys did not indicate any changes of
lipid and lipoprotein parameters which in humans are supposed to be associated with
an increased risk of cardiovascular lesions, namely a decrease in HDL- and increase
in LDL-cholesterol fractions.
The results of blood coagulation and fibrinolytic parameters showed increased antithrombin-III
and plasminogen levels besides minor changes in other parameters, thus indicating
that NET-Ac. -treatment does not contribute to an increased risk of cardiovascular
thrombotic events in the cynomolgus monkey.
Keywords
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Article info
Publication history
Accepted:
November 1,
1993
Received:
July 26,
1993
Identification
Copyright
© 1993 Published by Elsevier Inc.
