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Six Patterns of Drug-Drug Interactions

Dr. Armstrong is the Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Professor of Psychiatry, Oregon Health Sciences University, Portland, Ore. Dr. Cozza is the staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C., and Assistant Professor of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Md. Dr. Sandson is the Director of the Division of Education and Residency Training for the Sheppard Pratt Health System, Towson, Md., Associate Director of the University of Maryland/Sheppard Pratt Psychiatry Residency Program, Baltimore, and Clinical Assistant Professor in the Department of Psychiatry at the University of Maryland Medical System, Baltimore. Dr. Sandson is the author of Drug Interactions Case Book: The Cytochrome P450 System and Beyond (American Psychiatric Publishing, 2003). Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple St., Forest Grove, OR 97116; scott.armstrong{at}tuality.org (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ABSTRACT

The literature on pharmacokinetic drug-drug interactions usually focuses on various interactions relating to the cytochrome P450 system, phase II glucuronidation, and P-glycoprotein function. However, there has been relatively little examination of how the modes or patterns that govern these interactions can be systematically characterized to better anticipate drug-drug interactions in clinical practice. This article details a schema of six core patterns of pharmacokinetic drug-drug interaction relating to processes of induction and inhibition and the action of substrates. Case examples illustrating each pattern are provided.

Key Words: Drug-Drug Interactions

An important component of pharmacokinetic drug-drug interactions is the sequence(s) in which medications are added or removed from a patient's regimen. Medications are introduced, discontinued, and combined in complex ways for a variety of reasons. These sequences may be thought of as discrete "patterns" that can contribute to the formation of a drug-drug interaction. These patterns play a key role in determining if and when a clinically significant drug-drug interaction will occur.

Within the limits of our current knowledge base, we believe that six core sequential patterns characterize nearly all pharmacokinetic drug-drug interactions that involve the cytochrome P450 system, phase II glucuronidation, and/or P-glycoprotein function.

These patterns relate to processes of induction, inhibition, and the action of substrates. Before these patterns are described, definitions of these components are needed.

Inhibition is the process in which a drug slows down the normal activity level of a metabolic enzyme. The process can be competitive or noncompetitive, but it is usually immediate once the inhibitor is introduced and usually ceases once the inhibitor is cleared from the body. A drug that causes enzyme inhibition is called an "inhibitor."

Induction is the process in which a drug drives up the production of metabolic enzymes. The process usually takes several weeks to occur and involves new protein synthesis. The process can be reversed and production of metabolic enzymes returned to normal, in several weeks, if the drug that started the process is discontinued. A drug that causes enzyme induction is called an "inducer."

A substrate is a drug or compound that is identified as a metabolic target of a particular enzyme. A substrate, then, is always identified with a particular enzyme or a group of enzymes (for example, clozapine, which is metabolized by cytochrome P450 1A2, is a substrate of 1A2).

The Six Patterns

Pattern 1: Inhibitor Added to a Substrate
This pattern generally results in an increase in the serum level of the original drug or substrate. If the substrate has a low therapeutic index, then toxicity may result unless the clinician exercises particular care by closely checking the patient's blood levels and/or lowering the dose of the substrate in anticipation of the interaction.

For example, the addition of paroxetine, which is a 2D6 inhibitor,¹ to nortriptyline, which is a cytochrome P450 2D6 substrate,² impairs the ability of 2D6 to metabolize nortriptyline, leading to an increase in the blood level of nortriptyline.

We have observed this example in several patients. In one situation, a patient who had been receiving 100 mg/ day of nortriptyline had a stable serum level of 90 ng/ml. Paroxetine was then added to the patient's regimen and was clinically titrated to a dose of 40 mg/day. The patient then experienced palpitations and dizziness. An ECG revealed that the patient had a mild sinus tachycardia without any notable conduction blockade. The patient's subsequent serum nortriptyline level rose fourfold to 359 ng/ml. The patient fortunately did not have serious consequences, which could occur with such high tricyclic levels.

Pattern 2: Substrate Added to an Inhibitor
This pattern is the reverse of pattern 1 and may lead to new drug/substrate toxicity if the substrate has a low therapeutic index and is titrated according to preset guidelines that do not take into account the presence of an inhibitor. If the substrate is titrated until a specific blood level or therapeutic effect is achieved or with an appreciation that an inhibitor is present, then toxicity is less likely to arise. Accordingly, titration to a specific blood level and/ or clinical effect will tend to lead to use of lower doses of the substrate than would have been used had the inhibitor not been present.

For example, this pattern occurs when buspirone is added to nefazodone. Buspirone is a cytochrome P450 3A4 substrate,³ and nefazodone is a 3A4 inhibitor.⁴ Since nefazodone inhibits the ability of 3A4 to metabolize buspirone, the added buspirone generates a significantly higher blood level than would occur if the nefazodone were not already present. Undesirable side effects of buspirone may result unless appropriate caution is taken.

This pattern is illustrated by the case of a patient who had been taking an established dose of 600 mg/day of nefazodone for depression and anxiety. A modest starting dose of 5 mg of buspirone twice a day was added to the patient's medication regimen. This combination produced severe fatigue and headache in this patient. The Serzone® package insert⁵ stated that coadministration of buspirone and nefazodone can produce up to a 20-fold increase in buspirone blood levels! Hence, this patient may have been exposed to the equivalent of nearly 200 mg/day of buspirone, which would obviously produce unwanted side effects.

Pattern 3: Inducer Added to a Substrate
Addition of an inducer to a substrate generally results in a decrease in steady-state drug/substrate serum levels. This decrease may result in a loss of efficacy of the substrate, unless blood levels are monitored and/or the substrate doses are increased in anticipation of the interaction.

This pattern occurs, for example, when St. John's wort is added to cyclosporine. Cyclosporine is a 3A4 and P-glycoprotein substrate,^6,7 and St. John's wort is a 3A4 and P-glycoprotein inducer.^8–10 The induction of 3A4 by St. John's wort leads to more efficient liver metabolism of the cyclosporine, while the increase in available P-glycoprotein in the gut leads to decreased cyclosporine absorption. These two influences act together to produce a decrease in the cyclosporine blood level. This interaction has been reported and has led to both cardiac and renal transplant rejections.^11,12

Pattern 4: Substrate Added to an Inducer
Addition of a substrate to an inducer may lead to ineffective dosing if the clinician follows preset dosing guidelines that do not take into account the presence of an inducer. If the new drug/substrate is titrated to achieve a specific blood level or clinical effect or with an appreciation that an inducer is present, then dosing is more likely to be effective. Accordingly, titration to a specific blood level and/or to clinical effect will tend to lead to use of higher doses of the substrate than would have been used had the inducer not been present.

For example, this pattern occurs when quetiapine is added to phenytoin. Quetiapine is primarily a 3A4 substrate,¹³ and phenytoin is an inducer of several cytochrome P450 enzymes, including 3A4.¹⁴ Thus when quetiapine is introduced with phenytoin already present, there may be as much as a fivefold increase in clearance of quetiapine, leading to a significantly lower quetiapine blood level than would occur if the phenytoin was not present.¹⁵

This pattern is illustrated by the case of a patient with schizophrenia and a seizure disorder who had been taking 400 mg/day of phenytoin and had serum levels of the drug ranging between 10 and 14 µg/ml. Numerous trials of antipsychotics, including quetiapine titrated to an eventual dose of 900 mg/day, had failed for this patient. Once the possibility of a drug-drug interaction was recognized as a probable cause for the lack of antipsychotic efficacy, the patient was transitioned from taking phenytoin to taking valproate, which generally does not induce most liver enzymes. After this change, his psychotic symptoms improved while he was taking 600 mg/day of quetiapine.

Pattern 5: Removal of an Inhibitor, Causing Reversal of Enzyme Inhibition
Coadministration of a substrate and an inhibitor for a long period of time allows a steady state to be achieved. Subsequent discontinuation of the inhibitor leads to a resumption of normal enzyme activity and generally results in a decrease in the serum level of the substrate. This may result in the loss of efficacy of the substrate unless the clinician monitors the patient's blood levels and/or increases the dose of the substrate in anticipation of the reversal of inhibition.

This pattern is illustrated by the case of a liver transplant patient who had been taking prednisone, which is a 3A4 substrate,¹⁶ and fluconazole, which is a moderate 3A4 inhibitor.¹⁷ The discontinuation of fluconazole in the presence of prednisone resulted in the cessation of 3A4 inhibition. Normal enzymatic 3A4 activity ensued, and the patient's prednisone serum level decreased. The sudden drop in the blood level of prednisone led to an Addisonian crisis¹⁸ in this patient.

Not all reversals of inhibition produce such clinically dire consequences. However, loss of the clinical efficacy of the substrate after the inhibitor is removed is often not recognized by the treating clinician. The clinician unfortunately may assume simply that the substrate has somehow lost its effectiveness; yet all that is required for continued clinical efficacy is to increase the dose of the substrate.

Pattern 6: Removal of an Inducer, Causing Reversal of Enzyme Induction
This pattern occurs when an inducer is discontinued after a substrate and an inducer have been coadministered for a long period of time and steady state has been achieved for both compounds. Discontinuation of the inducer gradually—usually in 1–3 weeks—results in a reduction of metabolic enzymatic activity, leading to increased levels of the substrate. If the substrate has a narrow therapeutic index, drug toxicity may occur, unless the clinician monitors the patient's blood levels and/or decreases the dose of the substrate in anticipation of the reversal of induction.

This pattern may occur when a patient ceases cigarette smoking while taking a stable and clinically effective dose of clozapine. Clozapine is a 1A2 substrate,¹⁹ and cigarette smoking induces 1A2.^20,21 The smoking cessation results in a gradual decrease to "normal" 1A2 enzymatic activity. The patient's clozapine serum level can then increase, potentially to toxic levels.

Reversal of induction has been implicated in a number of cases of clozapine toxicity, which have produced seizures and other adverse events. Myers²² described clinical outcomes at a state psychiatric facility where a smoking ban was instituted. Eleven patients who were taking clozapine were monitored clinically and with tests of serum blood levels before and after the smoking ban was instituted. The mean increase in the patients' serum clozapine levels was 72% after the smoking ban, with one patient experiencing an increase of more than three times the toxic level. We believe that this study and others^23,24 suggest that psychiatric facilities may need to reconsider the wisdom of smoking bans for psychiatric inpatients who are either starting to take or already taking clozapine. This pattern may also be true for olanzapine,²⁵ of which 30%–50% is metabolized by 1A2. Another major concern would be that the dose of clozapine would be titrated without the presence of the inducer, smoking, while the patient was an inpatient, only to have the clozapine serum level drop below a therapeutic range if the patient resumed smoking as an outpatient (pattern 3).

Finally, another issue to address within these drug-drug interaction patterns is the action of pro-drugs. Pro-drugs are agents that are inactive as substrates and require conversion to an active metabolite to provide clinical efficacy. When considering pro-drugs, such as tramadol,^26,27 the clinical concerns for each of the described patterns are actually reversed. For instance, the concern in pattern 1 becomes the loss of efficacy rather than the development of toxicity, and the concern in pattern 3 becomes toxicity rather than loss of efficacy.

Conclusions

Familiarity with these six different patterns of drug-drug interaction is important in helping clinicians predict and recognize such interactions. Patterns 1 and 3 are straightforward and are therefore simple to detect. Patterns 2 and 4 are subtler and thus may pose more of a recognition challenge for the clinician. Patterns 5 and 6, however, can appear counterintuitive, especially when the discontinued medication has no intrinsic functional relationship to either target symptoms or emerging side effects. Unless one actively considers the paradigm that the discontinuation of particular medications within a regimen can produce unwanted difficulties (loss of efficacy or toxicity), then these issues are likely to elude detection. Pharmacy computer programs that alert clinicians to drug interactions and maintain patient medication lists can reasonably assist in addressing interactions that follow patterns 1–4. However, no currently available programs will alert clinicians to the interactions (or "uninteractions") that occur in patterns 5 and 6, yet these patterns can be critically important for patients' outcomes. At present, there is still no substitute for the application of human attention and intelligence to our patients' care.

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