plasma levels of propranolol than men following
single oral dosing and, in an additional study,
showed that on multiple dosing, propranolol steady
state (trough) plasma levels were 80% higher than
in men (Walleet al., 1985). This is probably
because propranolol is metabolized through three
pathways, but in women, the P450 cytochrome
oxidation pathways are less effective than in men
(Walleet al., 1989).
Methaqualone metabolism has been shown to
be significantly increased at the time of ovulation
(day 15), almost double than that of day 1, and this
was reflected in an area under the curve (AUC)
reduced by half on day 15. It is of interest that men,
used as a control, only sustained levels at the level
of day 1 in women (Wilsonet al., 1982).
Both verapamil and erythromycin appear more
effective in women than in men; this may be due to
higher blood levels resulting from differences in
liver metabolism and reduced glycoprotein trans-
portation (Meibohmet al., 2002).
Differences between males and females in the
amount of free drug found in plasma, and of
protein binding, have been reported for diazepam
(Abelet al., 1979; Greenblattet al., 1979) and
for imipramine (Kristensen, 1983). In the latter
instance, a direct correlation was found with
differences in lipoprotein and orosomucoid protein
(1-a-acid glycoprotein) fractions (Greenblattet al.,
1980). In women, oxazepam has been found to be
eliminated at a slower rate, about 10%, and for
temazepam about 25% (Divollet al., 1981). Chlor-
diazepoxide was also found to be less bound to
protein and this was even further reduced if women
were also on estrogen OCs (Robertset al., 1979).
Free lignocaine levels in women were 11% higher
in estrogen OC users, and 85% of this effect was
due to the reduction of the orosomucoid protein
fraction (Routledgeet al., 1981).
Circulating hormones, such as aldosterone and
renin, have long been known to fluctuate with the
menstrual luteal phase. If an amenorrheic cycle
occurs, these changes are not seen (Michelakis
et al., 1975). If OCs are given, then an increase of
these hormones is also seen in the first part of the
cycle (M’Buyamba-Kabungaet al., 1985). Andro-
gens transported on theb-globulin and albumen
fraction are influenced by estrogen, which
increases their binding. This effect is enhanced
by the use of OCs (Clarket al., 1971).
In animals, estrogen has been shown to influence
the effect of antidepressants on the brain. Wilson
showed that estradiol increased the binding of imi-
pramine to the uptake of serotonin at membrane
sites. Estrone had no effect, but the addition of
progesterone to low doses of estrogen increased
this effect. In all, the greatest effect seen was
about a 20% enhancement of imipramine binding
(Wilsonet al., 1986).
For low therapeutic/toxic drugs such as lithium,
this might prove to be an explanation of the reduc-
tion in efficacy seen at the end of the menstrual
cycle, when these hormone levels fall (Conrad and
Hamilton, 1986). It might also explain the reduc-
tion in efficacy of other central nervous system
drugs such as antiepileptics (Shavitet al., 1984;
Roscizeweskaet al., 1986) and antimigraine med-
ications, seen with the fluctuation of the menstrual
cycle (Gengoet al., 1984).
Young women appear to be the group most at
risk of developing extrapyramidal reactions when
taking the antinausea drug metoclopramide. This
appears to be strongly age- and gender-related
(Simpsonet al., 1987). Another age- or gender-
related effect is seen in older women who have
become newly postmenopausal and who are still
taking antipsychotic medications, because the
symptoms of tardative dyskinesia may appear or
even worsen (Smith and Baldessarini, 1973). This
is perhaps another example of the loss of estrogen
protection.
Many of the examples quoted involve central
nervous system drugs. This is very important, as
gender-related prescription usage is heavily
weighted in this area toward women. The FDA
1985 drug utilization report showed that for ben-
zodiazepines, the increased usage in women out-
numbers men by 2:1 (339 vs. 171 prescriptions/
1000 women and men, respectively). Twice as
many women are treated for depression and anxi-
ety neurosis than men, first described by Raskin
(1974), and confirmed by Weissman and Klerman
(1977). It is by no means certain that this is
solely due to biochemical differences, for women
are more likely to seek help than men. Of impor-
tance from theprior discussion is that,if women are212 CH16 DRUG DEVELOPMENT RESEARCH IN WOMEN