107the loss-of-function CYP 2C192 variant (rs4244285). Findings in the PAPI Study
were extended by examining the relation of CYP2C192 genotype to platelet func-
tion and cardiovascular outcomes in an independent sample of 227 patients under-
going percutaneous coronary intervention. Platelet response to clopidogrel was
found to be highly heritable. The relation between CYP2C192 genotype and
platelet aggregation was replicated in clopidogrel-treated patients undergoing cor-
onary intervention. It was concluded that CYP2C192 genotype is associated with
diminished platelet response to clopidogrel treatment and poorer cardiovascular
outcomes.
Lansoprazole and Cytochrome P450
The acid-inhibitory effect of lansoprazole depends on differences in cytochrome
P450 (CYP) 2C19 genotypes. CYP2C19 genotype status, as well as the grade of
gastroesophageal refl ux disease (GERD) before treatment, is one of the determi-
nants for the success or failure of treatment of GERD with lansoprazole. The low
cure rate in patients with the homozygous extensive metabolizer genotype appears
to be a result of these patients having the lowest plasma lansoprazole levels among
the various genotype groups.
Glucose-6-Phosphate Dehydrogenase
Phenotypes demonstrating variations in people’s response to certain drugs were fi rst
discovered in the early 1950s when antimalarial drugs were found to cause hemoly-
sis in patients with glucose-6-phosphate dehydrogenase (G6PD) defi ciency. G6PD,
expressed in all of the body’s tissues, controls the fl ow of carbon through the pen-
tose phosphate pathway, produces NADPH for reductive biosynthesis, and main-
tains oxidation-reduction in the cell to keep glutathione in a reduced state. The
absence of reduced glutathione due to G6PD defi ciency allows oxidative drugs to
oxidize sulfahydroxyl groups of hemoglobin, leading to hemolysis. Currently, over
two dozen drugs, including primaquine, sulfones, sulfonamides, nitrofurans, vita-
min K analogues, cefotetan, and chloramphenicol, are known to cause hemolytic
anemia in G6PD-defi cient patients. G6PD defi ciency is a sex-linked (chromosome
X) recessive trait and a widespread polymorphism, with more than 400 known vari-
ants and affecting more than 400 million people worldwide. However, the vast
majority of affected individuals are asymptomatic. Only 30 different functional
mutations in the gene have been reported, virtually all of which are found in the
region of the gene that codes for the protein. All but one are point mutations, with
more than 50 % being nucleotide conversions from cytosine to guanine. The conse-
quence of these genetic polymorphisms is low G6PD activity, resulting in reduced
glutathione concentrations in erythrocytes and subsequently clinical manifestation
of hemolytic anemia following the ingestion of certain drugs.
Role of Pharmacogenetics in Pharmaceutical Industry