Cytochromes: A Primer for Child and Adolescent Psychiatrists

CLINICAL

Associate Editor: Michael S. JeLLinek, M.D .

PERSPECTIVES

Child and adolescent psychiatrists, given the pace ofresearch, are hard-pressed to keep up with scientific progress relevant to their clinicalwork. Even with a medicalschool background. the knowLedge base for understanding highly technical journal papers may be outmodedor too limited. we hope that Clinical Perspectives such as this one by Oesterheld and Shader toill help clinicians stay abreast ofscientific, especiaLly biological, advances relevant to their d4ily practice. Just as this article wiLL add to clinicians' appreciation of the genetic and environmental interactions relevant to drug metabolism, occasional Clinical Perspectives in the ftture ioillfocus on advances in immunology, imaging, genetics, etc., in a manner directly relet/ant to clinicalpractice. M.S.j.

Cytochromes: A Primer for Child and Adolescent Psychiatrists JESSICA R. OESTERHELD, M.D.,

There has been an avalanche of information about cyrochromes (CYPs) and psychotropic drugs. The three vignettes that follow exemplify the importance of CYPs in drug interactions. Vignettes

1. A teenager is receiving phenytoin for treatment of a seizure disorder. Becauseof symptoms of a major depression, 20 mg of Huoxetine is started . Two weeks later, somnolence, ataxia, and nystagmus develop. Her blood levels of phenytoin have increased 150%. 2. A teenager with schizophrenia is treated with halo peridol for several months. Carbamazepine is added to help control aggressive outbursts. Oral dyskinetic movements develop on the third day. 3. A child with attention-deficit/hyperactivity disorder is treated with imipramine, 5 mg/kg. A family physician adds erythromycin to treat a streptococcal pharyngitis. Two days later the child experiencesvisual hallucinations and confusion. This article will review basic concepts of CYPs. will clarify why the above drug interactions occurred, and will present a simplified table that will enable the practicing child psychiatrist to better anticipate drug interact ions based on CYPs. Acapud November 17, 1997. Dr. Oesterheld isAssistantProfmor. Divisionof Child Prychiarry, Uniuersity of South Dakota School of Medicine, Sioux Falls. Dr. Shad~r is PrOftlSOr. DepartmentofPharmacology and Experimental Tberapeutia, TUftl University School of'Medicine, BOlton. Thepreparation ofthis work waslupporrtdin part bygrantMH 34233 ftom the Department of H~alth and Human Services. The authors thank David]. Grunb/arr, M.D., and David Osier; MD. , for their thoughrjUl review ofthis pap~r.

Reprin:requeus to Dr. O~surh~ld, DivisionofChild Prychiarry, University of South Dakota School ofMedicine, 911 E 20th Street, Sioux Fa/h, SD 57105. 0890·8567/98/3704-0447/S03.00/0 © 1998 by the Amer ican Academ y of Child and Adolescent Psychiatry.

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AND

RICHARD 1. SHADER, M.D.

What are CYPs?

First identified 50 years ago, CYPs are key enzymes that enable us to metabolize both endogenous and exogenous substrates. Found in all plants and animals, CYPs are located primarily in liver and small intestine, and also in the lungs, brain , kidney, and other organs . There are two classes of CYPs. Endogenous CYPs are found in mitochondria and are involved in metabolism of the body's own steroids, prostaglandin , and cell wall proteins. Exogenous CYPs are found in the smooth endoplasmic reticulum and metabolize toxins, carcinogens , mutagens, and drugs, including psychotropic drugs. Most of the known CYPs fall into this latter group. CYP refers to the enzyme as well as the gene that codes for the enzyme. The amino acid sequences of the major CYPs have been determined. A classification system based on grouping CYPs by degree of similarity of amino acid structure has been developed: family by Arabic number which share 40% amino acid sequencing (l to 4); subfamily by letter which share 55% amino acid sequencing (A to E); and isoform (specific enzyme) by Arabic number (l, 2, etc.), Think of a designation of your own house by city, street, and house number. Individual CYPs that have been identified as involved primarily in human drug metabolism include CYP IAl/2, CYP 2C9, CYP 2CI9, CYP 206, CYP 2EI, and CYP 3A4/5 (closely related enzymes are grouped together) . Developmental Aspects of CYPs

CYPs come "on line" throughout fetal life, and they have crucial roles in the growth. development, and protection of the fetus. By the end of the first postnatal year, CYPs are similar to those in adults, but they may have greater metabolic capacity. This can explain why prepubertal children require higher doses of psychotropics metabolized by the liver than do adults. Adult dosing requirements are established around

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puberty, and it is possible that pubertal CYP reductions in metabolic capacity explain the dosing reductions. The Exogenous CYPs: Chemical Actions

Exogenous CYPs transform drugs through a series of steps: phase I and phase II reactions. Oxidative metabolism is the major phase I reaction which provides "a handle" for further modification; others include hydrolysis and reduction. The products of this group of reactions are made more watersoluble (polar), and they are attached (conjugated) to chemical groups (e.g., glucuronide or sulfate, by another set of enzymes, phase II reactions) (Fig. 1) and excreted or, in some cases, directly excreted in the urine. Most psychotropic drugs undergo phase I and phase II reactions; exceptions are lorazepam and oxazepam, which undergo only phase II. Other exceptions are lithium, which is not metabolized, and drugs such as amantadine, which are partly eliminated in their unchanged form, or methylphenidate, which is primarily metabolized by gut and plasma esterases to an inactive form. Some drugs are routinely metabolized almost exclusively by a single CYP (e.g., nortriptyline or desipramine [OMI], secondary tricyclic antidepressants via CYP 206). Other drugs such as imipramine and clomipramine (CMI) (tertiary tricyclic antidepressants) require multiple CYPs. For example, CMI is demethylated to desmethyl-CMI with varying contributions from CYP 3A4/5, CYP lAl/2, and CYP 2C19, and then desmethyl-CMI is hydroxylated by CYP 206. Some CMI is also directly hydroxylated by CYP 206. Many factors influence the drug-CYP interaction: the substrate's affinity for the CYP, the concentration of the drug present, and the amount of the particular CYP that is available. Genetic Polymorphism

Genetic factors can influence the extent of metabolism of drugs (e.g., 7% to 10% of Caucasians have a genetic deficiency of enzymatically active CYP 206 and are less efficient in metabolizing drugs that are substrates of CYP 206, including many psychotropic agents, e.g., OMI, nortriptyline, ~-blockers, venlafaxine). For these individuals, blood levels of CYP 206 substrate drugs may be very high because the un metabolized drug is slowly cleared from the blood. By contrast, only 1% to 2% of Asians share this genetic poly-

Drug

morphism. Not only are there "slow rnetabolizers" of CYP 206, but there are a small number of "ultrafast" metabolizers who can have low blood levels of CYP 206 substrates. This trait may be more highly represented in Ethiopians. In addition, some Asian children and adults have a variant of this CYP which causes them to be intermediate or "somewhat slow" metabolizers; therefore, they can require lower dosing of OMI to achieve adequate blood levels. CYP 2C19 also is genetically polymorphic: 2% to 5% of Caucasians and 18% to 23% of Japanese are slow metabolizers via this CYP (Bertilsson, 1995). The clinical significance of other CYP polymorphisms is not known. Drug Interactions: Inhibitors and Inducers

Drugs that interact with CYPs can either inhibit, induce, or have no effect on the activity of the CYP. If a CYP is inhibited, substrates of that CYP will be metabolized less rapidly, and more unmetabolized drug will enter the circulation, leading to increased levels of the drug. Conversely, if a CYP is induced, additional CYP enzyme will be available for metabolism, leading to lower drug levels in the blood. Inhibition happens rapidly as soon as the inhibitor is present. However, induction takes some time to start (3 to 10 days) or stop (5 to 12 days) since protein synthesis must first occur and then cease. An inducer could initiate the process and yet no longer be present when the induction occurs. In the second vignette, the addition of carbamazepine, a potent inducer of several CYPs, has reduced levels of haloperidol, and the patient experiences withdrawal dyskinesias. There are many types of CYP inhibition. The following are two of the most common types: (1) competitive-two drugs compete for the same binding site with only one being metabolized (with enough drug one can overcome the inhibition); and (2) "mechanism-based"-the metabolites of drugs such as cimetidine or erythromycin, the most commonly used macrolide antibiotic, complex with and tie up the CYP (von Rosensteil and Adam, 1995). In the third vignette, erythromycin has complexed with CYP 3A4/5, and the level of imipramine, a substrate of CYP 3A4/5, has increased. The child demonstrates central anticholinergic toxicity from increased imipramine levels. CYP inhibition is quite complex. Not every drug from a class has the same potency (affinity) for the same CYP. Among the selective serotonin reuptake inhibitors, for

oxidation via CYP sulfatlon via transferase I Metabollte-O I Metabolite-O-su"ate --+ urine or bile Phase 2 Phase 1

Fig. 1 Exogenous microsomal oxidation followed by sulfation. CYP = cytochrome.

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CLINICAL PERSPECTIVES

TABLE 1 Cytochrome Table (Representative Agents) CVP

IAI/2

2C9

2CI9

206

3A4/5

Clinically relevant inhibitors

Cimetidine Ciprofloxacin Fluvoxamine

Cimetidine Fluconazole Fluoxetine Fluvoxamine Mephenytoin Ritonavir

Fluoxetine Fluvoxamine Ritonavir

Dexrropropoxyphene Fluoxetine Norfluoxetine Isoniazid Paroxetine Quinidine Ritonavir Thioridazine

Cimetidine Oiltiazem Erythromycin Fluconazole Grapefruit juice Indinavir Itraconazole Keroconazole Nefawdone Norfluoxetine Propoxyphene Ritonavir

Clinically relevant inducers

Broccoli etc. Charbroiled food Cigarettes

Carbamazepine Phenobarbital Rifampin

Rifampin S-Mephenytoin

Phenobarbital

Carbamazepine Phenylbutazone Phenobarbital Primidone Rifampin

Substrates

Aminophylline Caffeine (3A4/S,2EI) Clomipramine (2CI9, 3A4/5, 206) Clozapine (3A4/S,2CI9) Metoclopramide (206)

Amitriptyline (2CI9, 3A4/S, 206) Fluoxetine NSAIOs Phenytoin (lA1I2, 206) Propanolol (lA1I2, 2C19, 206) S-Warfarin

Amitriptyline Amphetamines Antiarrhythmics (2C9, 3A4/S, 206) Clozapine (3A4/5, IAII2) Antidepressants D iazepam (3A4/S) Des ipramine Imipramine Mircazepine (lA1I2, 206, 3A4/S) (lA1I2,3A4/S) S-Mephenytoin Nortriptyline Venlafaxine (3A4/S) Antipsychotics

Mirrazepine

~-Blockers

(206, 3A4/S) Olanzapine (206) Theophylline (3A4/S,2EI)

Chlorpheniramine Codeine Dextrornerhorphan Isoniazid (Methylphenidate) (esterases)

Antibiotics Ooxycycline Macrolides Rifampin Anticonvulsants Carbamazepine Ethosuximide Trimethadione Antidepressants Bupropion (2B6) Citralopam (2CI9) Mirtazepine (lAII2,206) Nefawdone Trazodone Tertiary TCAs Anripsychotics Clozapine (lAII2,2CI9) Pimozide Benwdiazepines/

zolpidern (lAI/2.206) AJprazolam Clonazepam Diazepam (2CI9) Midazolam Cisapride Hormones/steroids Anticancer Nonsedating antihistamines

Asrernizole Loratadine Opioids

Alfenranil NOt(: Probably many heterocyclic drugs, including many antipsychotics and many antidepressants, have alternative pathways. NSAIOs = nonsteroidal anti-inflammatory drugs; TCAs = tricyclic antidepressants.

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example. paroxetine has high potency as an inhibitor of CYP 206 and fluvoxamine is comparably high for CYP 1A1/2 and CYP 2C19. The addition of fluvoxamine to CMI increases levelsof CMI because dernethylation is inhibited. In practice. dosing of CMI needs to be reduced to one third if fluvoxamine is added. Concentration (how much of a drug is present) also influences CYP inhibition. One CYP may handle low concentrations of a given drug while another CYP kicks in when higher concentrations are present. Certain metabolic steps may also determine how fast a reaction occurs (rate limiting) and have major effects on metabolism. If a drug has several CYP pathways, it can be relatively protected against inhibition. However. protection is not afforded when drugs are added to a substrate that inhibits all pathways. In the first vignette, fluoxetine (and its active long half-lived metabolite norfluoxetine) inhibit CYP 2C9, the major pathway of phenytoin metabolism, as well as the minor pathways, CYP 1A1 and CYP 206. Maximal inhibition of these CYPs is achieved only as norfluoxerine reaches steady state. Thus, there is a delayed increase of phenytoin levels to clinical toxicity. There is an absolute ceiling to inhibition. When paroxetine, a strong inhibitor of CYP 206. is given to a child taking OM!, the effect is the same as would occur if a child, a slow metabolizer of CYP 206, were given OM!. Even foods can act as inhibitors and inducers of CYPs. Broccoli. cabbage. and other cruciferous vegetables induce the metabolism of CYP lA1I2. Theoretically, if a child taking CMI ate large amounts of broccoli, levels of CMI would decrease. A single 8-ounce glass of grapefruit juice added to CMI can double or triple CMI levels through its inhibition of CYP 3A4/5 and to a lesser extent. CYP 1A1I2 (Oesterheld and Kallepalli, 1997).

biotics, antihistamines, and anticonvulsants in children are not well known by child psychiatrists (Gillum et al.• 1993; Grange et al., 1994; Levy, 1995). they have been specificallyincluded in the table. Where known, principal pathways are unlabeled, and alternative pathways are designed by parentheses. Using the Table

When adding a new agent to an existing medication, a clinician can use this chart to anticipate drug interactions between agents. If both agents are listed on the same CYP (the same vertical column), a drug interaction is more likely. Blood levels could be affected depending on whether the medications are inhibitors, inducers, or substrates. For example, fluvoxamine (a competitive inhibitor of CYP 1A1I2) can significantly increase the plasma levelof clozapine (a substrate of CYP 1A1I2). Conversely, bupropion levelscan be decreased when carbarnazepine, an inducer of CYP 3A4/5, is added. The CYPs are only one of several sources of possible drug interactions; others can occur via interference with absorption, protein binding. or pharmacodynamically, at the receptor or beyond. Only clinical experience (published or otherwise) can confirm drug interactions not yet known to be therapeutically significant. This simplified table encompasses only some of the known CYP inhibitors, inducers, and substrates. The metabolic pathways of many commonly used medications have not yet been studied. It is hoped that clinicians will use this table to begin to understand and to organize the torrent of information on CYPs and drugs interactions that will surely follow.

REFERENCES Pediatric Cytochrome Table

There is an exploding literature regarding CYPs and their inhibitors, inducers. and substrates (Shader et al., 1995). It is increasingly difficult to remember all of these drug interactions. Table 1 presents five CYPs and selected common pediatric and psychotropic drugs metabolized by each cytochrome. CYP 2E1 has been omitted because no common pediatric psychotropic drug is a substrate of this system. The most common potent inhibitors and inducers of CYPs are organized alphabetically by CYP. Some pediatric and psychotropic drugs that are substrates of a CYP are grouped together under the potent inhibitors and inducers. Because CYP-based drug interactions between psychotropic medications and anti-

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Berrilsson L (1995), Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes P450 (CYP) 206 and 2C19. C/in Pbarmacokinet 29:192-209 Gillum JG. Israel OS, Polk RE (1993), Pharrnacokineric drug interactions with antimicrobial agents. C/in Pbarmacokinet 25:450-482 Grange JM, Winstanley PA, Davies PO (1994). Clinically significant drug interactions with antituberculosis agents. Drug Sa! II :242-251 Levy RH (1995). Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia 36(suppl 5):S8-S 13 Oesterheld JR, Kallepalli R (1997), Clomipramine and grapefruit juice: changing the rnerabolitic ratio (letter). J Clin PsychopharmacoI17:62-63 Shader RI, von Molrke LL, Schmider J. Harmatz JS, Greenblatt OJ (1995). The clinical and drug interactions: an update (editorial). J Clin Psychopharmacol 16:197-201 von Rosensreil NA, Adam 0 (1995), Macrolide antibacterials: drug interactions of clinical significance. DrugSa[ 13:105-122

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