DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

A
TPMT Activity, U/ml
B
30
25
20
15
10
5
0
Screens of Human Tissue
Preclinical Functional Studies
TPMT*1
0 2 h 4 h 8 h 16 h 24 h
TPMT*2
0 20 40 1 h 4 h 8 h
TPMT*1/*1
TPMT*1/*2
TPMT*1/*3A
TPMT*1/*3C
TPMT*1S/*3C
TPMT*3A/*3C
TPMT*2/*2
TPMT*2/*3A
TPMT*3A/*3A
Stable
t
1
2
= 0.35 h
TPMT
C
Incidence of Required
dosage decrease
D
Incidence of Relapse
1
0.5
0
0
0.8
0.6
0.4
0.2
Clinical Phenotype/Genotype
Association Studies
homozygous variant
0.5 1 1.5 2 2.5
Time in Years
heterozygote (N=15)
0
0 2 4 6 8 10
Time in Years
heterozygote
wild-type (N=231)
wild-type
165
CHAPTER 7
PHARMACOGENETICS
Figure 7–14. Three primary types of evidence in pharmacogenetics. Screens of human tissue (A) link phenotype (thiopurine
methyltransferase activity in erythrocytes) with genotype (germline TPMT genotype). The two alleles are separated by a slash (/);
the ∗1 and ∗1S alleles are wild-type, and the ∗2, ∗3A, and ∗3C are nonfunctional alleles. Shaded areas indicate low and intermediate
levels of enzyme activity: those with the homozygous wild-type genotype have the highest activity, those heterozygous for at least
one ∗1 allele have intermediate activity, and those homozygous for two inactive alleles have low or undetectable TPMT activity
(Yates et al., 1997). Directed preclinical functional studies (B) can provide biochemical data consistent with the in vitro screens of
human tissue, and may offer further confirmatory evidence. Here, the heterologous expression of the TPMT∗1 wild-type and the
TPMT∗2 variant alleles indicate that the former produces a more stable protein, as assessed by Western blot (Tai et al., 1997). The
third type of evidence comes from clinical phenotype/genotype association studies (C and D). The incidence of required dosage
decrease for thiopurine in children with leukemia (C) differs by TPMT genotype: 100%, 35%, and 7% of patients with homozygous
variant, heterozygous, or homozygous wild-type, respectively, require a dosage decrease (Relling et al., 1999). When dosages of
thiopurine are adjusted based on TPMT genotype in the successor study (D), leukemic relapse is not compromised, as indicated by
comparable relapse rates in children who were wild-type vs. heterozygous for TPMT. Taken together, these three data sets indicate
that the polymorphism should be accounted for in dosing of thiopurines. (Reproduced with permission from Relling et al., 1999.
Copyright © Oxford University Press.)
three different anticancer drugs, 11 individual drug
regimens can easily be generated.
Nonetheless, the potential utility of pharmacogenetics
to optimize drug therapy is great. After
adequate genotype/phenotype studies have been conducted,
molecular diagnostic tests will be developed,
and genetic tests have the advantage that they need
only be conducted once during an individual’s lifetime.
With continued incorporation of pharmacogenetics
into clinical trials, the important genes and
polymorphisms will be identified, and data will
demonstrate whether dosage individualization can
improve outcomes and decrease short- and long-term
adverse effects. Significant covariates will be identified
to allow refinement of dosing in the context of
drug interactions and disease influences. Although the
challenges are substantial, accounting for the genetic
basis of variability in response to medications is
already being used in specific pharmacotherapeutics
decisions, and is likely to become a fundamental component
of diagnosing any illness and guiding the
choice and dosage of medications.