associated with high levels of Von Willebrand fac-
tor (Folsomet al., 1999), found commonly in the
Black population sickle cell anemia, thalassemia
and glucose dehydrogenase deficiency are
ethnically linked, but how do they effect drug
metabolism?
The small genetic variation (DNA), only 0.5 of
the 11% total variations between individuals
of these groups among the three major divisions
of humans (Caucasian, Negroid and Mongoloid),
makes up the total variation between individuals
of these groups (Vessell, 1989). Thus, it would
not be a surprise if race gives rise to fewer differ-
ences than does individual variation of drug
metabolism and dynamics. That is, genes ofrace
have less influence than an individual’s total
geneticmake-up.
PK/PD and ethnic differences
One of the earliest reports of differences was
described by Chen and Poth (1929). They noted
that the mydriatic response to cocaine was greatest
in Caucasians, less in Chinese and least in Blacks.
When PK differences were first reported in
the literature, they usually involved the genetic
polymorphisms of acetylation, the debrisoquine–
sparteine and mephenytoin pathways, the second
phase of metabolism or selective protein transport
systems. Drugs such as clonazepam, hydralazine,
sulphonamides, isoniazide, nitrazepam and procai-
namide undergo acetylation in the liver. Most
Asians, especially Japanese (88–93%), are fast
acetylators compared to 50% of Caucasians and
Blacks (Wood and Zhou, 1991). Fast acetylators
may be at greater risk of isoniazide hepatitis from
toxic metabolites (Drayer and Reidenberg, 1977),
whereas slow acetylators may respond better to
treatment (sustained levels) but be at greater risk
of toxic reactions. Those drugs which extensively
use both acetylation as to second phase of metabo-
lism, and also use either of two cytochomes
enzymes in the first phase, are more likelyto induce
Lupus (Hess, 1982) and/or hypersensitivity reac-
tions (Reider, 1999). The two cytochromes were
identified as CYP2D6 and CYP2C19, part of the
extensive P450 cytochrome enzyme systems not
only found mainly in the liver but also present in
other tissues such as gut, lung and brain. Ethnic
differences in these two pathways have also been
found, CYP2D6 enzymes are lacking in 8% of
Caucasians and 1% of Asians. CYP2C19 is lacking
in 20% of Asian, 4–8% of Blacks and 3% of
Caucasians. These are two of the three commonest
first phases, metabolic pathway. The most common
CYP3A4 has not demonstrated Ethnic sensitivity.
Perpherazine and over-the-counter (OTC) ingre-
dients codeine and dextromethorphan are made
active by the debrisoquine–sparteine oxidative
pathway. The percentage of an ethnic or racial
population poorly metabolizing by this pathway
varies greatly; for example Switzerland 9–10%,
Hungary 10%, United States 7%, Nigeria 3–8%
and Japan 0.5% (Wood and Zhou, 1991), but if not
will gain no pain relief.
Clinically, this has been shown to make a differ-
ence in a small study in males, involving 10 Chinese
and 9 Caucasian subjects; the Chinese metabolized
propranolol more rapidly, clearance was 76%
higher, with a lower area under the curve (AUC)
and plasma levels lower than that in the Caucasians
at all time points. In this study, when dosage was
adjusted upwards to equilibrate to Caucasian
therapeutic blood levels, a greater response was
noted in the Chinese subjects (lower blood pressure
and pulse rate) (Zhouet al., 1990). Conversely, the
presence of very fast metabolizers in a population
may also vary.
The mephenytoin metabolic pathway is utilized
by commonly used drugs, such as mephobarbital,
hexobarbital, diazepam, imipramine and omepra-
zol, but only 3–5% of Caucasians and 8% of Blacks
are poor metabolizers of mephenytoin, compared
to 15–20% of Chinese and Japanese populations
(Kupferet al., 1988). This enzyme’s activity is
inhibited by floconazole and fluoxetine and
induced by drugs such as barbiturates and nicotine
(smoking).
The lack of digestive enzyme lactase in many
Hispanics, especially Mexican-Americans and
African-Americans, causes lactose intolerance,
with nausea, diarrhea and occasionally vomiting.
It is understandable that lactose is no longer pre-
ferred as a filler (non-active excipient) in tablets
and capsules.234 CH18 RACIAL AND ETHNIC ISSUES IN DRUG REGISTRATION