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33

Drugs that are able to increase the gastric transit, such as metoclopramide due to its

prokinetic properties, may accelerate gastric emptying, resulting in decreased

absorption of drugs such as digoxin or theophylline.

Altered Drug Transport

Transport proteins, which are present in the intestinal mucosa, are important

considerations in clinically relevant DDIs.

37 Some proteins are involved in the

transport of compounds from the lumen of the intestine into the portal bloodstream,

whereas others are involved in the efflux of compounds from the intestinal mucosa

back into the gut lumen. The efflux transporters, particularly a specific glycoprotein,

which resides in the cell membrane, P-glycoprotein (P-gp), are the most well known.

P-gp is an ATP-dependent transporter that is genetically encoded and located on the

apical surface of mucosal cells in the intestine, generally in increasing concentration

from the stomach to the colon. In addition, P-gp is also present on a number of

lymphocyte subsets and within the brain capillary endothelial cells. The primary role

of P-gp is to limit systematic drug exposure, pumping compounds from the inside of

the cell back into the gut lumen, into renal tubules in the kidney, and into bile in the

liver. Given its presence in various anatomic locations, drug-induced modulation of

P-gp activity may affect the absorption and/or distribution of a coadministered

substrate medication. There are several drugs that are known to block the action of Pgp and

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are known as P-gp inhibitors, and there are drugs that have been shown to cause

induction of P-gp. Coadministration of a P-gp substrate with an inhibitor increases

the amount of substrate available for absorption and may result in an elevated serum

drug concentration. For drugs such as rifampin that increase expression of P-gp (i.e.,

P-gp inducer), the coadministration of a substrate results in an enhanced efflux of the

substrate into the gut lumen and lowers serum concentration of the substrate.

DISTRIBUTION

CASE 3-1, QUESTION 2: Describe the interaction of warfarin and phenytoin based on protein binding.

Following administration and absorption, drugs are distributed throughout the

body.

37,38 While some drugs have near-complete dissolution in the plasma, drugs such

as warfarin and phenytoin are highly bound to protein (primarily to albumin) with the

same affinity binding sites (Figure 3-1). Drugs that are highly protein bound (>90%),

those with a NTI, and those with a small volume of distribution are more likely to

result in significant drug interactions.

Warfarin can be displaced from protein-binding sites by drugs such as phenytoin.

Although this displacement occurs quickly with rapid changes in serum warfarin

levels, typically this interaction is not clinically significant. Warfarin that is

displaced from protein-binding sites is readily available for elimination by hepatic

metabolism, resulting in increased clearance without a significant change in the free

drug concentration. Because warfarin’s anticoagulant action takes several days due to

the long half-lives of some of the vitamin K-dependent clotting factors, warfarin

equilibrium is re-established before a new steady state can be reached for these

clotting factors.

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METABOLISM

Pharmacokinetic interactions that involve changes in metabolism are a common cause

of clinically significant drug interactions. Drug metabolism is divided into two

general categories: phase I and phase II reactions.

37,38 Phase I reactions involve

intramolecular changes including oxidation, reduction, and hydrolysis, which

increases the polar nature of the drug, generally making it less toxic. Phase II

reactions generally involve combining a phase I product with an endogenous

substance resulting in glucuronidation, sulfation, acetylation, and methylation, and

primarily results in termination of biologic activity of the drug.

39,40 The main enzymes

that are responsible for drug-metabolizing systems in phase I reactions are the

cytochrome (CYP) 450 enzymes, which play a key role in many therapeutically

important drug interactions.

1,2 Drugs that are metabolized by the same CYP450

enzyme family, when administered concurrently, may interact with each other as a

result of induction or inhibition.

39,40 Of the human CYP450 enzyme family, the 6

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.

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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.