Page 83 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 4 Drug Biotransformation 69

a single nucleotide polymorphism (SNP) within intron 3, which muscle relaxant may become susceptible to prolonged respiratory
enables normally spliced CYP3A5 transcripts in 5% of Caucasians, paralysis (succinylcholine apnea). Similar pharmacogenetic differ-
29% of Japanese, 27% of Chinese, 30% of Koreans, and 73% of ences are seen in the acetylation of isoniazid. The defect in slow
African Americans. Thus, it can significantly contribute to inter- acetylators (of isoniazid and similar amines) appears to be caused by
individual differences in the metabolism of preferential CYP3A5 the synthesis of less of the NAT2 enzyme rather than of an abnor-
substrates such as midazolam. Two other CYP3A5 allelic variants mal form of it. Inherited as an autosomal recessive trait, the slow
that result in a PM phenotype are also known. acetylator phenotype occurs in about 50% of blacks and whites in
Polymorphisms in the CYP2A6 gene have also been recently the USA, more frequently in Europeans living in high northern lati-
characterized, and their prevalence is apparently racially linked. tudes, and much less commonly in Asians and Inuit (Eskimos). The
CYP2A6 is responsible for nicotine oxidation, and tobacco smok- slow acetylator phenotype is also associated with a higher incidence
ers with low CYP2A6 activity consume less and have a lower inci- of isoniazid-induced peripheral neuritis, drug-induced autoimmune
dence of lung cancer. CYP2A6 1B allelic variants associated with disorders, and bicyclic aromatic amine-induced bladder cancer.
faster rates of nicotine metabolism have been recently discovered. A clinically important polymorphism of the TPMT (thio-
It remains to be determined whether patients with these faster purine S-methyltransferase) gene is encountered in Europeans
variants will fall into the converse paradigm of increased smoking (frequency, 1:300), resulting in a rapidly degraded mutant enzyme
behavior and lung cancer incidence. and consequently deficient S-methylation of aromatic and hetero-
Additional genetic polymorphisms in drug metabolism are cyclic sulfhydryl compounds including the anti-cancer thiopurine
being discovered. Of these, the gene for CYP2B6 has become drugs 6-mercaptopurine, thioguanine, and azathioprine, required
noteworthy as one of the most polymorphic P450 genes, with a for their detoxification. Patients inheriting this polymorphism as
20- to 250-fold variation in interindividual CYP2B6 expression. an autosomal recessive trait are at high risk of thiopurine drug-
Despite its low (1–5%) contribution to the total liver P450 con- induced fatal hematopoietic toxicity.
tent, these CYP2B6 polymorphisms may have a significant impact Genetic polymorphisms in the expression of other phase II
on the CYP2B6-dependent metabolism of several clinically rel- enzymes (UGTs and GSTs) also occur. Thus, UGT polymorphisms
evant drugs such as cyclophosphamide, S-methadone, efavirenz, (UGT1A1*28) are associated with hyperbilirubinemic diseases
nevirapine, bupropion, selegiline, and propofol. Of clinical rel- (Gilbert’s syndrome) as well as toxic effects due to impaired drug
evance, women (particularly Hispanic-American women) express conjugation and/or elimination (eg, the anticancer drug irinotecan).
considerably higher hepatic levels of CYP2B6 protein than men. Similarly, genetic polymorphisms (GSTM1) in GST (mu1 isoform)
Studies of theophylline metabolism in monozygotic and dizy- expression can lead to significant adverse effects and toxicities of
gotic twins that included pedigree analysis of various families have drugs dependent on its GSH conjugation for elimination.
revealed that a distinct polymorphism may exist for this drug and
may be inherited as a recessive genetic trait. Genetic drug metabo- C. Role of Pharmacogenomic Testing in Clinically Safe &
lism polymorphisms also appear to occur for aminopyrine and car- Effective Drug Therapy
bocysteine oxidations. Regularly updated information on human Despite our improved understanding of the molecular basis of
P450 polymorphisms is available at http://www.cypalleles.ki.se/. pharmacogenetic defects in drug-metabolizing enzymes, their
Although genetic polymorphisms in drug oxidations often impact on drug therapy and ADRs, and the availability of vali-
involve specific P450 enzymes, such genetic variations can also dated pharmacogenetic biomarkers to identify patients at risk, this
occur in other enzymes. Recently, genetic polymorphisms in clinically relevant information has not been effectively translated
POR, the essential P450 electron donor, have been reported. In to patient care. Thus, the much-heralded potential for personalized
particular, an allelic variant (at a 28% frequency) encoding a POR medicine, except in a few instances of drugs with a relatively low
A503V mutation has been reported to result in impaired CYP17- therapeutic index (eg, warfarin), has remained largely unrealized.
dependent sex steroid synthesis and impaired CYP3A4- and This is so even though 98% of US physicians are apparently aware
CYP2D6-dependent drug metabolism in vitro. Its involvement in that such genetic information may significantly influence therapy.
clinically relevant drug metabolism, while predictable, remains to This is partly due to the lack of adequate training in translating this
be established. Descriptions of a polymorphism in the oxidation knowledge to medical practice, and partly due to the logistics of
of trimethylamine, believed to be metabolized largely by the genetic testing and the issue of cost-effectiveness. Severe ADRs are
flavin monooxygenase (Ziegler’s enzyme), result in the “fish- known to contribute to 100,000 annual US deaths, about 7% of
odor syndrome” in slow metabolizers, thus suggesting that genetic all hospital admissions, and an increased average length of hospital
variants of other non-P450-dependent oxidative enzymes may stay. Genotype information could greatly enhance safe and effica-
also contribute to such polymorphisms. cious clinical therapy through dose adjustment or alternative drug
therapy, thereby curbing much of the rising ADR incidence and its
B. Phase II Enzyme Polymorphisms associated costs. (See Chapter 5 for further discussion.)
Succinylcholine is metabolized only half as rapidly in persons with
genetically determined deficiency in pseudocholinesterase (now Commensal Gut Microbiota
generally referred to as butyrylcholinesterase [BCHE]) as in persons
with normally functioning enzyme. Different mutations, inherited It is increasingly recognized that the human gut microbiome
as autosomal recessive traits, account for the enzyme deficiency. can also significantly influence drug responses. It thus serves as
Deficient individuals treated with succinylcholine as a surgical another relevant source of therapeutic misadventures and adverse