Some drugs, such as phenothiazines and tricyclic
antidepressants, show greater preference for bind-
ing and transport ona–1 acid glycoprotein rather
than on albumin. Thus, 44% of Swiss and both US
White and Black populations have higher levels of
this protein, compared to 15–27% of the Japanese
population (Eap and Bauman, 1989; Mendoza,
1991). This might explain the higher fraction of
free drug found in Asians (with a greater volume
ofdistributionandclearance),aswellasthefactthat
themetabolismofsomebenzodiazepinesappearsto
be slower in Asians than in Caucasians (Kumana
et al., 1987). One study (Zhanget al., 1990) showed
that Chinese subjects who were either poor or
extensive mephenytoin metabolizers when taking
diazepam (mephenytoin pathway) still metabolized
diazepam at the same rate as Caucasian poor meta-
bolizers. The higher proportion of slow metaboli-
zers of mephenytoin pathways is thus not the only
difference. However, ethnic differences in the per-
centage of body fat between the two groups could
also account for this. The ‘p’ protein transport
system is also being explored for ethnic drug
variations, especially in the maintenance of the
blood–brain barrier.
As previously noted, drugs such as propranolol
and imipramine each have two major pathways,
and even poor metabolizers of any significant path-
ways usually have alternative pathways, which
might be expected to show some increased hand-
ling ability over time. Thus, in many cases, plasma
levels and clinical differences between poor and
good polymorphic metabolizers may be insignif-
icant. In others, especially where the therapeutic
index is small, it may be critical – usually these
drugs are titrated for efficacy and safety and thus,
the effect is avoided. In other cases, such as anti-
hypertensive agents, the clinical effect of genetic
differences may not be seen, because the patient’s
dosage is titrated to blood pressure response
(Eichelbaum and Gross, 1990) and only a large
meta-analysis may show ethnic optimal dosage.
Prescribing differences
Of great concern are findings that ethnicity may
affect prescribing habits. Sleathet al.(1998) looked
at the patient’s ethnicity and the likelihood of
a psychotropic being prescribed: they found that
Caucasians received medication 20% of the time
and non-Whites only 13.5%. A similar finding was
made by Khandker and Simoni-Wastilia (1998)
concerning any prescription drug. Differences
werefoundatallages,withBlackchildrenreceiving
2.7 fewer prescriptions than their Caucasian coun-
terparts. This rose to 4.9 prescriptions in adult
Blacks and 6.3 in elderly Blacks. All the patients
were on Medicaid, so ability to pay was not a factor.
Dinsdaleet al.(1995) confirmed a similar pattern in
prescriptionsissuedforanalgesicsforpostoperative
pain to be self-administered by the patient, with
Caucasians receiving prescriptions significantly
more frequently than minorities (p¼0.01).Genetic and ethnic susceptibility
Therapeutic effects may vary between ethnic popu-
lations, due either to a sizeable representation of
poor metabolizers present or to a genetic or ethnic-
related ‘susceptibility’. Clozapine is associated
with the development of agranulocytosis in 20%
of Ashkenazi Jews, compared to 1% of the general
population treated for schizophrenia. This was
found to be highly associated with specific linked
genes for agranulocytosis and especially those of
Ashkenazi Jewish origin (100%) (Leibermanet al.,
1990). Yet again, the best known example was the
sensitivity to quinine and its derivatives in Blacks
given to prevent malaria, resulted in many deaths in
World War II.
Another example of PD differences is that of
reports on lithium in the manic phase of bipolar
depression. Asian patients, including Japanese,
are reported to have therapeutic blood levels at
0.5–0.8 m.eg/l compared to required levels in US
Caucasian patients of 0.8–1.2 m.eg/l (Takahashi,
1979; Jeffersonet al., 1987; Yang, 1987); these
findings, however, are disputed by Changet al.
(1985). African-Americans require less drug, but
this is because of higher levels due to a slower
clearance rate than Caucasians (Linet al., 1986;
Jeffersonet al., 1987).
Asians have been reported to require smaller
doses of neuroleptic drugs and to suffer adverse18.3 OBJECTIVE DIFFERENCES 235