13

Genotype concordance with predicted phenotype has also been found to be lower in

pediatric patients.

20 Additionally, ethnic variation among study results also suggests

that testing may be more beneficial in certain groups, namely those with Asian

ancestry. As is the case when using ethnicity to determine whether or not to complete

any genetic test, self-reported ancestry is not always a reliable means of predicting

someone’s actual genetic lineage. With the generation of promising preliminary

studies, a continued focus on NAT2 genotype effects on isoniazid safety has the

potential to result in institutions and organizations adopting policies to proactively

test NAT2 in the context of isoniazid treatment to both prevent adverse drug events

and increase treatment success in the future.

PHARMACODYNAMIC IMPLICATIONS

CASE 4-2

QUESTION 1: E.F. is a 51-year-old male status post ST elevation myocardial infarction (STEMI) and atrial

fibrillation with a residual left ventricular thrombus. Despite aggressive dose escalations of warfarin, his

international normalized ratio (INR) will not budge above 1.7. His current dose of warfarin is 10 mg daily and

he reports no dietary changes or excessive vitamin K intake. There are no drug–drug interactions identified in

his regimen. The cardiology team asks about pharmacogenomic testing. What are the known genes involved in

warfarin metabolism that would impact E.F.’s INR?

Table 4-1

NAT2 Genotypes and Phenotypes

NAT2 Allele Activity

Slow *5-7, *10, *12D, *14, *17, *19

Rapid *4 (wild type), *11, *12A-C, *13, *18

NAT2 Phenotype Summary

Genotype Acetylator Rate Clinical Manifestation with Isoniazid Therapy

Homozygous slow Slow Increased risk of adverse drug events

Heterozygous Intermediate

Homozygous rapid Fast/rapid Possible increased risk of treatment

aShown in a small number of studies.

13

p. 53

p. 54

Table 4-2

Summary of NAT2 Genotypes and Hepatotoxicity Risk with Isoniazid Studies

Study Study Type Population Metric Result

Sun et al.

14 Meta-analysis

N = 5 case–control

studies

133 cases

(hepatotoxicity)

492 controls

Chinese

Japanese

East Indian

Caucasian

Prevalence of SA

status in

hepatotoxicity cases

vs. control

Overall: no significant finding

Asian subgroup analysis:

↑ risk hepatotoxicity for SAs

OR 2.52 (CI 1.5–4.3)

Wang et al.

15 Meta-analysis

N = 14 case–

controlstudies

11 Asian, 3 nonAsian

474 cases

(hepatotoxicity)

1,446 controls

Japan

China

Taiwan

India

Korea

Turkey

Switzerland

USA (8%)

SA hepatotoxicity

risk vs. RA

↑ risk hepatotoxicity for SAs

OR_Asian: 4.9 (CI 3.3–7.1)

OR_non-Asian: 3.7 (CI 1.3–

10.5)

↑ risk hepatotoxicity in

combination regimen

Ben Mahmoud

et al.

16

Observational Case–

control

N = 65

Tunisian SA hepatotoxicity

risk vs. RA and IAs

↑ risk hepatotoxicity for SAs

OR 4.3; (CI 1.5–1

isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5

contribute to the metabolism of a vast majority of drugs compared with other enzymes

(Figure 3-2).

6,41-43 Examples of drug that induce enzymes are rifampin, phenytoin,

carbamazepine, St. John’s-wort, and nevirapine. Enzyme inducers cause an increase

in the synthesis of the enzyme(s) responsible for metabolism of the substrate drug.

The mechanisms of induction are complex involving presystemic metabolism via

induction of hepatic and/or intestinal drug-metabolizing enzymes, subsequently

reducing serum concentrations with a loss of pharmacologic activity of the drug. In

some cases, induction will increase the formation of metabolites that are

pharmacologically or toxicologically active.

1,43,44 There are many drugs that are

inhibitors of CYP450 including some drugs within these classes: statins, macrolide

antibiotics, antifungal azoles, fluoroquinolones, and HIV protease inhibitors.

Inhibition of drug metabolism slows down the rate of drug metabolism, resulting in

an increase in the amount of drug in the body and potential toxicity. Grapefruit juice

is an inhibitor of CYP3A4 and has been known to increase the bioavailability and

reduce the clearance of many drugs including HMG-CoA reductase inhibitors

(statins), calcium antagonists, HIV protease inhibitors, and immunosuppressant

agents.

45-48

Inhibition can be described as reversible or irreversible, with the

reversible ones being a more common process. There are three mechanisms of

reversible inhibition: competitive inhibition (competition between the inhibitor and

the substrate for the enzyme’s active site); noncompetitive inhibition (binding of the

inhibitor to a separate site on the enzyme, rendering the enzyme complex

nonfunctional); or uncompetitive inhibition (binding of the inhibitor only to the

substrate–enzyme complex, rendering it ineffective).

1,48,49

Irreversible inhibition

occurs when the perpetrator drug forms a reactive intermediate with the enzyme that

leads to a permanent inhibition of the enzyme. Irreversible drug interactions tend to

be more profound than those caused by reversible mechanisms. Examples of drugs

that are known to cause irreversible inhibition include macrolide antibiotics,

erythromycin, clarithromycin, paroxetine, and diltiazem.

15,50,51

CASE 3-1, QUESTION 3: The medical team starts N.M. on warfarin therapy postsurgery for

thromboembolism prophylaxis. The medical intern asks you to explain the mechanisms of drug interactions to

consider with the use of warfarin and phenytoin because N.M has been on phenytoin for the past 10 years and

her seizure disorder has been controlled on it.

Figure 3-1 Examples of drugs that bind to and compete for one of two sites, designation I and II, on albumin.

(Adapted from Drug Interactions. In: Rowland M et al, eds. Clinical Pharmacokinetics and Pharmacodynamics:

Concepts and Applications. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2011:490.)

There are two potential mechanisms for a warfarin (drug)–phenytoin (drug)

interaction. In early therapy, there could be a displacement of warfarin from proteinbinding sites by phenytoin (as described in the previous case question), and a

possible enhancement of the anticoagulant effect and risk for bleeding. This is

primarily a concern in patients with hepatic impairment. With prolonged therapy,

there could be a phenytoin-induced, CYP enzyme induction thereby enhancing

warfarin metabolism resulting in a decreased warfarin effect. INR monitoring on

postoperative days 1 through 5 will provide information on the impact of the DDI and

incorporation of a warfarin initiation guideline or algorithm will help adjust dosing

until a stable regimen is established. After the initial period, weekly INR monitoring

will provide information on enzyme induction and further adjustment of warfarin

doses.

p. 42

p. 43

Figure 3-2 Graphic representation of the different forms of cytochrome-P450 (circles) in humans with different

but some overlapping substrate specificities. The arrows indicate single metabolic pathways. Representative

substrates are listed above for each enzyme. Also listed are relatively selective inhibitors and inducers of the

enzymes. (Reprinted from Drug Interactions. In: Rowland M, Tozer TN, eds. Clinical Pharmacokinetics and

Pharmacodynamics: Concepts and Applications. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2011, with

permission.)

Warfarin is rapidly and completely absorbed after oral administration with the

proximal duodenum appearing to be the most likely location of absorption. Case

reports of warfarin malabsorption, whether acquired, related to surgery, or

inflammatory conditions, are rare.

52

The rate and extent of phenytoin absorption varies considerably among oral dosage

forms.

53 Phenytoin suspension is poorly absorbed when administered via feeding tube

with continuous enteral feedings.

54 The time to reach maximum plasma levels

increases with increasing dose.

55 This is a reflection of low phenytoin solubility and

capacity-limited metabolism. Therefore, a small change in the dosage form or

bioavailability, coupled with limited metabolism, can produce a large change in

plasma drug concentration.

56 GI surgery and GI inflammatory conditions (Crohn’s

disease, ulcerative colitis, scleroderma, etc.) can change the anatomy of the GI tract.

Alterations to surface area, gastric emptying time, gastric pH, and inflammation of the

intestinal lining may lead to abnormal plasma concentrations.

57

N.M.’s GI function is still preserved after orthopedic surgery. Warfarin

administration and absorption is unlikely to be impacted. She should continue on the

same phenytoin dose and formulation that she has been taking at home with

appropriate monitoring.

Pharmacokinetic interactions influencing the metabolism of warfarin and clinically

significant interactions are likely with warfarin use when its metabolism is induced

or inhibited.

48 Warfarin is a racemic mixture of R- and S-enantiomers. Interactions

involving agents known to influence the hepatic microsomal enzyme systems

responsible for the metabolism of the more potent S-enantiomer (CYP2C9) are more

significant than those that influence the enzymes that metabolize R-enantiomer

(CYP1A2, CYP3A4). Phenytoin is also predominately metabolized via the CYP2C9

enzyme and has been reported to interact with warfarin in a biphasic manner.

49-51

Genetic polymorphism also is a significant factor affecting warfarin dosing and

response. Nucleotide polymorphisms have been identified that influence warfarin

metabolism and sensitivity, including variants of CYP2C9 and variants in vitamin K

epoxide reductase complex (VKORC1).