Ethnic variations in diet, additives or salt content
may alter metabolism rates. Linet al.(1986) and
Henryet al.(1987) report that antipyrine metabo-
lism was different in rural Asian Indians than in
Asian Indian immigrants resident in England for
some years. Dietary environmental differences
may also account for the findings of Gouldet al.
(1972) and Katoet al.(1973) of a gradation of heart
and stroke incidence, lowest in residents of rural
Japan, higher in Japanese in Hawaii and highest in
Japanese in California.
High- or low-fat diets can affect ingestion of
drugs, as can a high intake of salt affect diuretic
efficacy. Findings that some spices may influence
metabolism have been reported. Bailyet al.(1991)
showed that enhanced bioavailability of felodipine
can be more than doubled, and to a lesser extent,
nifedipine, with concurrent consumption with
grapefruit juice compared to water (an effect not
seen with orange juice), and many other drugs
(Rau, 1997).
Age, height and weight differences
Currently, there is an obvious difference in average
height–weight of US/European citizens versus
Japanese. This reflects in a difference in blood/
tissue volume which alone probably accounts for
more real drug differences than pharmacogenetics
and other factors previously discussed. In the Uni-
ted States and Europe, from the largest normal to
the smallest normal males in terms of height and
weight, there is a 70% difference (Metropolitan
Life Insurance Tables, 1999). Add to this 30%
lower height–weight for the smallest normal-
sized female.
To compound this, the Japanese small normal
female is 20% smaller than her European counter-
part. Despite this, in general, blood level differ-
ences are not as great as might be supposed.
However, these regional size differences appear
to be decreasing as the average increase of height
in the United States is slowing, whereas in other
nations, such as Japan, they are increasing.
A final physiologic population difference to be
considered is the relative ages of the three popula-
tions: United States 32.9 years, Europe 34–38
years and Japan 38.2 years (World Almanac,
1992;World Population Prospects [by WHO],
1992). The differences between the average age
of the three populations may cause a slight ‘age
effect’ change in the average function of organs
such as kidney and liver and the metabolism and
excretion of drugs. Japan and Sweden have a
greater proportion of their population over 80
years compared to the other regions and this seg-
ment, whereas generally increasing worldwide, is
increasing faster in Japan.18.4 Subjective factors
The previousobjectivefactors can produce, on
occasion, a real although usually small/difference
in drug levels and effect. The next group of factors
to be discussed are largelysubjectivebut still have
an even more profound effect on protocol design,
execution, measurement, outcome, recording and
interpretation of the data collected. The subjective
biases of doctors, patients, study monitors, experts,
investigators and regulatory assessors are affected
in different ways by variations of the three regional
medical cultures and practices, and their popula-
tion cultural values. It is also an area which is
poorly researched by comparative studies. Many
of the observations reported in this next section
camefrom the experiences ofthe authororfrom the
literature of anthropology and social biology.Medical practice
Physicians in Japan try to achieve effectiveness
with no adverse effects with what, by US standards,
appear to be almost homeopathic doses at times.
In Europe, the aim is to achieve effectiveness
with some minimal side effects, often by titrating
the dose upwards. In the United States, the aim
is to achieve optimal effectiveness with accepta-
ble adverse effects and then titrate downwards.
Thus, the highest total daily dosage tends to be
greater in the United States than in the other two
regions.
The pressure to prescribe is greater in the United
States than in Europe; for example antibiotic usage238 CH18 RACIAL AND ETHNIC ISSUES IN DRUG REGISTRATION