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Several studies have shown ethnic differences in drug metabolism mediated by
CYP2D6 or CYP2C19 have been summarized elsewhere. In most western popula-
tions, 93 % are normal or effi cient metabolizers (EM), 7 % are poor metabolizers
(PM), and less than 1 % are ultrarapid metabolizers (UM) of CYP2D6. In contrast
to the Caucasians, only 1 % of the Orientals are PMs. PMs have a metabolic ration
(MR) greater than 12.6 and are homozygous for mutations. About 4 % of the
Caucasians are PMs of CYP2C19 as compared with about 20 % of the Orientals.
One allele (m 1 ) accounts for 75 % of PMs and Orientals have an additional unique
allele (m 2 ) accounting for 25 % of PMs. There is risk of adverse effects in PMs and
UMs due to abnormal serum levels of the drug. Ethnic factors, therefore, are an
important consideration in individualization of therapy.
There are major differences between ethnic groups in the frequency of CYP3A5
expression. For example, 30 % of Caucasians express CYP3A5 and more than 50 %
of African Americans express CYP3A5. Liver tissue from Caucasian and African
Americans carrying at least one CYP3A51 allele contains three times more
CYP3A than that from other individuals. The metabolism of a model drug (mid-
azolam) proceeded 2.5 times faster in Caucasians and 2.2 times faster in African
Americans with at least one CYP3A51 allele compared with metabolism in indi-
viduals homozygous for CYP3A5*3. Thus CYP3A5 may be the most important
contributor to interracial differences in CYP3A dependent drug clearance and
response to many medicines.
Gender Differences in Pharmacogenetics
There are gender-related differences in pharmacokinetics, which may be related to
pharmacogenetic differences in to drug-metabolizing enzymes. Men seem to have
a higher activity relative to women for the cytochrome P450 (CYP) isoenzymes
CYP1A2 and potentially CYP2E1, for the drug effl ux transporter P-glycoprotein,
and for some isoforms of glucuronosyltransferases and sulfotransferases. Women
were suggested to have a higher CYP2D6 activity. No major gender-specifi c
differences seem to exist for CYP2C19 and CYP3A. The often-described higher
hepatic clear ance in women compared with men for substrates of CYP3A and
P-glycoprotein, such as erythromycin and verapamil, may be explained by increa-
sed intrahepatocellular substrate availability due to lower hepatic P-glycoprotein
activity in women relative to men. Other gender differences in pharmacokinetics
may be due to fl uctuations in hormone levels in women with menstruation and
pregnancy.
For a few drugs, e.g. verapamil, beta-blockers and selective serotonin reuptake
inhibitors, gender-related differences in pharmacokinetics have been shown to
result in different pharmacological responses, but their clinical relevance remains
unproven. Moreover, development of diseases such as heart disease and cancer may
affect women differently from men. There is no data to support the effi cacy of
statins in preventing heart attacks and stroke in women with hypercholesterolemia,
partly because there have not been adequate representation of women in clinical
4 Pharmacogenetics