Pharmacokinetic Interactions

Given the large number of medications consumed by transplant recipients, it is no surprise that this patient population is at high risk for DDIs. Pharmacokinetic DDIs pose a major dilemma with the maintenance immunosuppressants. Pharmacokinetic interactions can either result in increased concentrations of one or more agents with an increased risk for drug-induced toxicities, or lowered (i.e., subtherapeutic) drug concentrations, possibly leading to allograft rejection. As mentioned above, pharmacokinetic DDIs can be further categorized into interactions of absorption, distribution, metabolism, and elimination.

Interactions of Absorption

Most DDIs due to altered absorption occur within the intestines. There are a variety of potential mechanisms through which the absorption of the maintenance immunosup-pressants is altered, including:

• Drug metabolism within the gut ("Interactions of Metabolism" will be discussed below)

• Alterations in the active transport process

• Changes in intestinal motility

• Chelation interactions

Active transporters (i.e., P-glycoprotein [P-gp]) play an important role in drug-interactions. P-gp, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys.42, 3 This protein provides a biological barrier, eliminating toxic substances and xenobiotics that may accumulate in these organ systems. P-gp plays an important role in the absorption and distribution of many medications. In the GI tract, P-gp is located in the brush borders of mature enterocytes. The colon has the largest percentage of P-gp, while the stomach and jejunum-ileum contain the lowest percentage. P-gp affects the absorption of cyclosporine, tacrolimus, and sirolimus. Some medications can alter the activity of P-gp (inhibit or induce its activity). Medications that are cytochrome P450 (CYP) 3A4 substrates, inhibitors or inducers, also tend to affect P-gp; therefore, the potential exists for several DDIs with the immunosuppress-ants by this mechanism.42,43 For example, medications that inhibit P-gp activity will increase concentrations of cyclosporine, tacrolimus, and sirolimus due to a reduction in P-gp-dependent drug elimination from the hepatic circulation.

When looking at the ability of drugs that change intestinal motility and their effects on the maintenance immunosuppressants, you can see notable interactions between the prokinetic agents and the calcineurin inhibitors. Metoclopramide has been shown to increase the absorption of cyclosporine and tacrolimus by enhancing gastric mobil-44

ity and emptying.

Most of the interactions with mycophenolate mofetil and enteric-coated MPA are due to reductions in intestinal absorption. Aluminum, magnesium, and calcium containing products decrease the peak level of MPA.9 If a patient requires aluminum, magnesium, or calcium, it should be administered at least 4 hours before or after MPA. Of note, iron does not interact with the MPA preparations.45

Interactions of Distribution

Interactions of distribution tend to occur with drugs that are highly protein bound. A drug that is extensively bound to plasma proteins can be displaced from its binding site by another agent that has greater affinity for the same binding site, thereby raising free concentrations of the displaced drug. MPA is the only highly protein bound

(97% bound to albumin) maintenance immunosuppressant with a reported DDI by this mechanism. It has been shown that concomitant administration of MPA with salicylates increases the free concentrations of MPA.9 The adverse sequelae of this drug interaction have not been assessed. DDIs studies have not been completed evaluating the MPA derivatives, or the other highly protein bound maintenance immunosuppress-ants, when used with other highly protein bound drugs.

Interactions of Metabolism

Oxidative metabolism by CYP isozymes is the primary method of drug metabolism.46 The purpose of drug metabolism is to make drugs more water-soluble so they can be more easily eliminated. Cyclosporine, tacrolimus, and sirolimus are all substrates of the CYP3A isozyme system. The majority of CYP-mediated metabolism takes place in the liver; however, CYP is also expressed in the intestine, lungs, kidneys, and brain. Two types of interactions usually occur with medications metabolized via the CYP enzyme system, inhibitory interactions and inducing interactions. Enzyme inhibition occurs when there is enzyme inactivation or mutual competition of substrates at a catalytic site. This usually results in a reduction of drug metabolism leading to increased concentrations of all medications involved. Enzyme induction interactions are just the opposite and occur when there is increased synthesis or decreased degradation of CYP enzymes. This type of interaction can produce decreased concentrations of medications.46 Being CYP3A substrates, it would be anticipated that cyclosporine, tacrolimus, and sirolimus would all experience similar pharmacokinetic DDIs. Table 55-6 details the clinically relevant DDIs that occur with the calcineurin inhibitors and sirolimus due to inhibition or induction of the CYP isozyme system.

One of the most often overlooked DDIs in transplant recipients is the effect cor-ticosteroids have on drug metabolism. Dexamethasone is a CYP3A isozyme inducer, meaning that it may increase the whole blood trough concentrations of cyclosporine, tacrolimus, and sirolimus.9,47 Conversely, methylprednisolone is a CYP3A isozyme inhibitor, and it may reduce the whole blood trough concentrations of cyclosporine, tacrolimus, and sirolimus.9,47 This is usually not a noteworthy interaction, since doses of cyclosporine, tacrolimus, and sirolimus are titrated to achieve target concentrations in patients maintained on stable doses of corticosteroids. However, these DDIs may be problematic after pulse dose steroids for treatment of acute rejection or during steroid withdrawal.

Not all metabolic DDIs occur through the CYP system. Azathioprine has a considerable interaction with allopurinol that is not mediated through CYP.48,49 Allopurinol inhibits xanthine oxidase, which is the enzyme responsible for metabolizing 6-MP to inactive 6-thiouricate. Combining these agents can result in 6-MP accumulation and severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if necessary, azathioprine doses must be reduced to one-third or one-fourth of the current dose.4

Interactions of Elimination

There are very few interactions of elimination with the maintenance immunosup-pressants. However, the major interaction through this process involves MPA. MPA is metabolized to MPA-glucuronide (MPAG) via hepatic glucuronosyltransferase.9,28 MPAG is excreted in the bile for elimination in the gut. Deconjugation of MPAG

back to MPA by intestinal flora results in a secondary absorption of MPA several

9,28

hours after its administration. ' Several medications have been shown to interfere with the biliary excretion of MPAG, thereby eliminating its reabsorption in the intestines and lowering the overall exposure to MPA. Cyclosporine has been shown to reduce the overall exposure to the MPA derivatives through competitive inhibition of MPAG enterohepatic recirculation.50 MPA levels are lower when it is administered in cyclosporine-based immunosuppression regimens compared to tacrolimus-based regimens. The bile acid sequestrants (i.e., cholestyramine, colestipol, colesevelam) have

51,52

also been shown to decrease overall MPA exposure through a similar mechanism. Pharmacodynamic Interactions

In addition to the numerous pharmacokinetic interactions seen with the maintenance immunosuppressants, there also exists the possibility for pharmacodynamic interactions. An in-depth review of pharmacodynamic interactions with maintenance immun-osuppressive agents goes beyond the scope of this chapter. However, some common pharmacodynamic DDIs will be discussed. Pharmacodynamic interactions are the backbone of modern immunosuppressive therapies that employ multiple medications with different mechanisms of action resulting in additive immunosuppression. Unfortunately, pharmacodynamic interactions can also be problematic, such as when medications with similar adverse events are used concomitantly. For example, nephrotoxic agents, such as amphotericin B, amino-glysides (i.e., gentamicin, tobramicin, amikacin) and non-steroidal anti-inflammatory drugs (NSAIDs; i.e., napro xen, ibuprofen, ketorolac) may potentiate the nephrotoxic effects of the calcineurin inhibitors.9 The use of myelosuppressive agents, such as cotrimoxazole and valganciclovir, could enhance the myelosuppressive effects of induction therapy and the maintenance immun-osuppressants.9

Table 55-6 Potential DDIs With the Calcineurin Inhibitors and Sirolimus Mediated Through the Cytochrome P-450 System 3A (CYP3A4) Isozyme

Subjt rales"

Inducers'1

Inhibitors'

Alfentarill

Alprazolam

Arnioifiiiont?

Amlodipine

Atorvastatin

CikKl^iDl

Cisapride

Chlofpromazifw

Clonazepam

Cocaine

Cortisol

Cyclophosphamide Dantrolene napsone

Diazepam

Dlsopyramlde

Enalripril

Estradiol

Estrogen

EtocosicTe

Fpfndipine

Flutamide

Lidocaine

Loratiidine

Nevirapine

Nicardipine

Nifedipine

Omepiaaole

Pjclitaael

Propafenone

Protjesteroi>e

Quetiapine

(JuinidinD

Sertuline

Simvastatin

Tamoxifen

Testosterone

Triazolam

Uenlafadne

Vinblastine

Warfarin

Zolpidem

Carbarnazeplne nteKamet hasona

Ethjosuximide

Isofïlazld

Nevirapine

Phénobarbital

Phenytoln

Prednisone

Mabulin

Rifampin

St. John's wort

Cirnetidine

C.larilhromycin

Clûi r irnazcile

Delavlrdlne

Diltia/em

Erythromycin

Fluconazole

Fluoxetine f-luvoxamine

Grapefruit juice

Indinavir

ItfJCDMJZOlC

KetocûnàZole

Miconazole

Nefazodonai

Nellinavir

Ritonavir

Saquinavir

Troleandomycin

Verapamil

Voriconazole

Zsf irtuk^sl

■^ubst rales cf theCYP3A4 isozyme will comjwle wllhcyclosporine, racroiirmiSvand skollnrnjsfor metabolism; therefore, concentrations of bolh medications will be increased (usually by less than or equal to 20%).

Inducers of the CYP3A4 isozyme will enhance the metabolism of cyclosporine, tacrolimus., and sirolimus; therefor, concentrations of these me* ileal Ions will be decrease,

Inhibitors of the CYP3A4 isozyme will decrease the metabolism of cyclosporine, tacrolimus, and sirolimus; therefore, concentrations of these medications will be increased^

The potential exists for multiple DDIs in transplant recipients due to the complexity of their medication regimens. Practitioners must be diligent in reviewing all medications for potential DDIs. In addition to reviewing prescription medications, it is essential to question patients about the use of both nonprescription and complementary and alternative medicines, as these products also have the potential for significant interactions.

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