Page 92 - Basic _ Clinical Pharmacology ( PDFDrive )

78 SECTION I Basic Principles

system (CNS). Morphine is 200 times more potent as an ago- CYP-mediated oxidation reactions (predominantly CYP2C19)
nist than codeine, and conversion of codeine into morphine is to the active thiol metabolite responsible for antiplatelet activity.
essential for codeine’s analgesic activity. The enzyme responsible Genetic polymorphisms in the CYP2C19 gene that decrease
for the O-demethylation conversion of codeine into morphine is active metabolite formation and consequently reduce the drug’s
CYP2D6. Patients with normal CYP2D6 activity (ie, EMs) con- antiplatelet activity are associated with variability in response to
vert sufficient codeine to morphine (∼5–10% of an administered clopidogrel. Carriers of the reduced function CYP2C19 *2 alleles
dose) to produce the desired analgesic effect. PMs and IMs are taking clopidogrel are at increased risk for serious adverse cardio-
more likely to experience insufficient pain relief, while UMs are vascular events, particularly in acute coronary syndrome managed
at an increased risk for side effects, eg, drowsiness and respiratory with percutaneous coronary intervention (PCI); the hazard ratios
depression, due to higher systemic concentrations of morphine. (HR) are 1.76 for *2/*2 genotype and 1.55 for *2 heterozygotes
Interestingly, gastrointestinal adverse effects, eg, constipation, are compared to noncarriers. The risk associated with stent thrombo-
decreased in PMs, whereas the central side effects, eg, sedation and sis is even greater (HR 3.97 for *2/*2 genotype and 2.67 for *2
dizziness, do not differ between PMs and EMs. The antitussive heterozygotes compared to *1 homozygotes). However, for other
properties associated with codeine are not affected by CYP2D6 indications, eg, atrial fibrillation and stroke, the effects of the
activity. According to CPIC guidelines, standard starting doses are CYP2C19*2 allele are less dramatic. Thus, current clinical recom-
recommended in EMs and IMs with close monitoring, especially mendations from CPIC are specific for acute coronary syndrome
in IMs; and CPIC recommends use of an alternative agent in PMs with PCI: Standard starting doses are recommended in EMs and
and UMs (see Table 5–2). UMs, and CPIC recommends use of an alternative antiplatelet
agent, eg, prasugrel or ticagrelor, in PMs and IMs (Table 5–2).
CYP2C19 The US Food and Drug Administration (FDA)-approved label for
clopidogrel recommends alternative antiplatelet drugs for patients
Cytochrome P450 CYP2C19 is known to preferentially metabo- who are poor metabolizers of clopidogrel.
lize acidic drugs including proton-pump inhibitors, antidepres-
sants, antiepileptics, and antiplatelet drugs (Chapter 4). Four Dihydropyrimidine Dehydrogenase (DPD)
clinical phenotypes related to CYP2C19 activity (PM, IM, EM,
and UM) are closely associated with genetic biomarkers that may Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD
assist in guiding individualized therapeutic dosing strategies. The gene) is the first and rate-limiting step in pyrimidine catabolism,
gene that encodes CYP2C19 is highly polymorphic, with over 30 as well as a major elimination route for fluoropyrimidine che-
alleles defined (www.cypalleles.ki.se/cyp2c19.htm), yet just four motherapy agents (Chapter 54). Considerable intergroup and
alleles can account for the majority of phenotypic variability, ie, intragroup variation exists in DPD enzyme activity. Many of the
CYP2C19 allele *2 and *3 are nonfunctional, CYP2C19 allele alleles identified in the DPYD gene either are too rare to suf-
*1 is fully functional, and CYP2C19*17 has increased function. ficiently characterize or have shown conflicting associations with
Phenotypes range from PMs who have two deficient alleles, eg, DPD activity. Three nonfunctional alleles have been identified, ie,
*2/*3, *2/*2, or *3/*3, to UMs who have increased hepatic DPYD *2A, *13, and rs67376798. All three of these variants are
expression levels of the CYP2C19 protein, due to *1/*17 or rare; however, the *2A allele is the most commonly observed allele
*17/*17 alleles (see Table 5–2). Of note, the *17 increased func- and is often the only variant tested in commercial genotyping
tion allele is unable to fully compensate for nonfunctional alleles, platforms (see National Institutes of Health Genetic Testing Reg-
and therefore, the presence of a *17 allele in combination with istry, http://www.ncbi.nlm.nih.gov/gtr/conditions/C2720286/ or
a nonfunctional allele would be considered an IM phenotype http://www.ncbi.nlm.nih.gov/gtr/conditions/CN077983/). Fre-
(see Table 5–2). The PM phenotype is more common in Asians quencies of the *2A allele range from less than 0.005 in most
(∼16%) than in Europeans and Africans (∼2–5%), which can European, African, and Asian populations to 3.5% in a Swedish
be expected based on the inheritance patterns of variant alleles population (see Table 5–1).
across populations, eg, the most common nonfunctional allele, Example: Three fluoropyrimidine drugs are used clinically,
ie, CYP2C19*2, is observed approximately twice as frequently in namely 5-fluorouracil (5-FU), capecitabine, and tegafur (only
Asians (∼30%) compared with Africans and Europeans (∼15%), approved in Europe). 5-FU is the pharmacologically active com-
while the apparent gain-of-function *17 allele is observed rarely pound of each drug, and all are approved to treat solid tumors
in Asians (< 3%) but more frequently in Europeans and Africans including colorectal and breast cancer (Chapter 54). 5-FU must
(16–21%) (see Table 5–1). be administered intravenously, while both capecitabine and
Example: Clopidogrel is a thienopyridine antiplatelet pro- tegafur are oral prodrugs that are rapidly converted to 5-FU in
drug indicated for the prevention of atherothrombotic events. the body. Only 1–3% of an administered dose of the prodrug is
Active metabolites selectively and irreversibly inhibit adenosine converted to the active cytotoxic metabolites, ie, 5-fluorouridine
diphosphate-induced platelet aggregation (Chapter 34). Clopido- 5′-monophosphate (5-FUMP) and 5-fluoro-2′-deoxyuridine-5′-
grel is metabolized in the body via one of two main mechanisms; monophosphate (5-FdUMP), which effectively target rapidly
approximately 85% of an administered dose is rapidly hydro- dividing cancer cells and inhibit DNA synthesis. The major-
lyzed by hepatic esterases to its inactive carboxylic acid deriva- ity of an administered dose (∼80%) is subjected to pyrimidine
tive, while the remaining ∼15% is converted via two sequential catabolism via DPD and is excreted in the urine. Complete or