a low toxicity ceiling (e.g. digoxin) where adjusted
dosing is required.
The weight/dose problem
A casual appraisal of ideal weight-for-height tables
for males and females (Metropolitan Life Insur-
ance, 1999) shows clear differences between males
and females. The mythical ‘average’ 70 kg (154
lbs), male would be 5^01000 in height and his female
counterpart 5^0400 and weight 130 lbs. This is a 28%
difference in weight. This mythical male is often
used to calculate dose ranges for ‘optimal’ dose
determinations, around which phase II and phase
III efficacy and safety studies evolve. Even more
striking is therangeofnormalheights and weights,
remembering that thesamedose is usually pre-
scribed to individuals across the range. In males,
this varies from 5^0 at 106 lbs to 6^0800 at 226 lbs; in
females, it varies from 85 lbs at 4^0900 to 185 lbs at
60500 ; yet all are ideal weights for their respective
heights. For both sexes, this represents a 46%
differential in healthy weight while taking the
same dose of medication. Why should these great
disparities be tolerated by the research community,
industry and agencies? Because most drugs
work – even over these ranges. First, the majority
of the population falls toward the middle of the
height–weight levels, rather than the extremes.
Second, most drugs have a wide range over
which they exert therapeutic effect before efficacy
levels off. Third, the level of unacceptable adverse
events generally occurs at much higher doses than
the therapeutic level for most drugs (there are some
notable exceptions, e.g. lithium, digitalis, warfarin,
etc.).
For lipophilic drugs, the composition of mass to
fat/total body water is a further variable, increasing
in women after puberty. The composition of ‘good
fat and bad fat’ changes with age, both in increased
fat, increased bad fat and its relocation to the fat
around the heart and abdomen. The quantity and
distribution differs between genders. This may
have an effect on lipid-soluble drugs, regarding
the level, the time to achieve steady state and the
time to eliminate the drug and its metabolites from
such fat storage depots.
Different gastric emptying time
Some studies have shown that women demonstrate
greater duration in the gastric residence time of
medications, which is reflected in an increased lag
time of absorption, compared to men. This effect is
increased when medication is taken with food,
even when adjusted for the timing of the menstrual
cycle (Majaverianet al., 1987).This was consistent
with other reports that men had faster emptying
times for both liquid and digestible solids than
women (Majaverianet al., 1988; Wrightet al.,
1983). The length of time and variability of gastric
emptying in women was also reported by Notivol
et al. (1984) to be altered in relation to the
menstrual cycle and was shortest at mid-cycle
(MacDonald, 1965; Boothet al., 1957).
These changes can affect the amount of drug in
the blood. Miaskiewiczet al.(1982) showed that,
after a single dose of sodium salicylate, absorption
was slower and achieved a lower level in women.
This has also been shown for ibuprofen. TheTmax
was observed to be more than 54 min in
females, compared to aTmaxof 31.5 min in males.
Majaverian even showed a delay of 9.5 h before
absorption occurred in one woman (Majaverian
et al., 1987). Sex differences in plasma salicylate
albumin binding capacity have been reported
(Miaskiewiczet al., 1982) and, for other agents
(Allen and Greenblatt, 1981),g-globulin transport
systems have been reported to be altered with the
menstrual cycle.
Some effects on absorption can be subtle, such
as the greater absorption of alcohol in women due
to their reduced gastric mucosal and liver alcohol
dehydrogenase activity compared to men. This
results in higher circulating levels of alcohol, in
spite of body weight corrections (Frezzaet al.,
1990), with obvious implications. Odansetron, on
the other hand, is more slowly metabolized by
women and thus may be more effective.Metabolic gender differences
Propranolol is still one of the most frequently used
bblockers (National Prescription Audit, 1989), but
Walleet al.(1985) reported that women had higher16.5 DRUG HANDLING DIFFERENCES BETWEEN MALES AND FEMALES 211