Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

104 Applying Pharmacogenomics in Therapeutics
Polymorphisms of the CYP family members have been taken into consideration
for adjusting drug doses. Practice guidelines need to be established to implement
the application of genetic laboratory test results into actionable prescribing
decisions for specific drugs. To address this need, a shared project, the Clinical
Pharmacogenetics Implementation Consortium (CPIC), was established by the
Pharmacogenomics Knowledgebase * and the National Institutes of Health–
sponsored Pharmacogenomics Research Network (PGRN) in 2009 (Gonzalez-
Covarrubias et al. 2009). Peer-reviewed gene–drug guidelines developed by this
consortium are published and updated periodically † based on new developments
in the field. For example, CPIC published a guideline for CYP2D6 and CYP2C19
genotype and dosing of the tricyclic antidepressants in 2013 (Hicks et al. 2013).
OTHER DRUG-METABOLIZING ENZYMES: TPMT, NAT, AND UGT1A1
Thiopurine Methyltransferase
Thiopurine methyltransferase (TPMT) is another example of an important genetic
polymorphism responsible for drug metabolism. TPMT catalyzes the S-methylation
of thiopurine drugs, such as 6-mercaptopurine (6-MP) and azathioprine (AZA),
that are cytotoxic immunosuppressive agents used to treat acute lymphoblastic leukemia
of childhood, inflammatory bowel disease, and organ transplant recipients
(Weinshilboum and Sladek 1980). The thiopurine drugs have a narrow therapeutic
window, and therefore the difference between the dose of the drug required to achieve
desired therapeutic effect and that causing toxicity is relatively small. The most serious
thiopurine-induced toxicity is life-threatening myelosuppression. The human TPMT
cDNA and gene were cloned and characterized in the 1990s (Honchel et al. 1993). The
most common TPMT variant allele in white populations is TPMT*3A (about 5%), an
allele that is predominantly responsible for the trimodel frequency distribution of the
levels of RBC TPMT activity (Krynetski et al. 1996; McLeod et al. 2000; Tai et al.
1996). TPMT*3A has two nonsynonymous SNPs, one in exon 7 and another in exon 10
of this 10-exon gene. The allozyme encoded by TPMT*3A is rapidly degraded by an
ubiquitin–proteasome-mediated process. The level of TPMT in the RBC reflects the
relative level of activity in other human tissues such as the liver and kidney. There are
striking differences in the frequency of variant alleles for TPMT. TPMT*3A is rarely,
if ever, found in East Asian populations but TPMT*3C, with only the exon 10 SNP,
is the most common variant allele in East Asian populations (about 2%) (McLeod
et al. 2000). Individuals with homozygous TPMT*3A are at greatly increased risk for
life-threatening myelosuppression when treated with standard doses of the thiopurine
drugs. Therefore, 1/10 to 1/15 of routine doses are prescribed to further avoid myelosuppression.
TPMT is the first example selected by the US FDA for a public hearing
on the inclusion of pharmacogenetic information in drug labeling. Clinical testing for
TPMT genetic polymorphism is widely available (www.prometheuslabs.com).
* PharmGKB; www.pharmgkb.org
†
http://www.pharmgkb.org