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- v.13(4); October 2000
- PMC1312247
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Proc (Bayl Univ Med Cent).October 2000; 13(4): 421-423.
doi:10.1080/08998280.2000.11927719
PMCID:PMC1312247
PMID:16389357
Chris C. Ogu, Pharm D
1EUJan L. Max, Rph1
Information about the author Copyright and license information Reserva
Abstract
Cytochrome P450 is a family of isoenzymes responsible for the biotransformation of various drugs. Drug metabolism mediated by the cytochrome P450 system has been shown to be an important determinant of several drug interactions that can result in drug toxicity, reduced pharmacologic effects, and adverse drug reactions. Recognizing whether the drugs in question act as substrates, inducers or inhibitors of enzymes can prevent clinically significant interactions. Avoiding co-administration or anticipating potential problems and adjusting the patient's treatment regimen early in therapy can ensure an optimal response with minimal side effects.
Drug metabolism mediated by the cytochrome P450 system has been shown to be an important determinant of several drug interactions. A greater degree of interaction predictability was achieved through the identification of P450 isoenzymes and some drugs that share them. Six different P450 isoenzymes - CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 - have been identified and play an important role in drug metabolism (1,2). Of these 6 isoenzymes, common metabolism of the CYP3A4 isoenzyme has led to several clinically significant drug interactions. More information about the effects of certain drugs on enzyme-mediated biotransformation led to the identification of enzyme inducers and inhibitors, providing even greater insight into the nature of the interactions.
Cytochrome P450 represents a family of isoenzymes responsible for the biotransformation of many drugs by oxidation. Enzymes are heme-containing membrane proteins that are found in the smooth endoplasmic reticulum of various tissues. Although most isoenzymes are found in the liver, extrahepatic metabolism also occurs in the kidneys, skin, gastrointestinal tract, and lungs. Significant inactivation of some orally administered drugs is due to extensive first-pass metabolism in the gastrointestinal tract by CYP3A4 (3).
FACTORS AFFECTING BIOTRANSFORMATION
Many factors influence the biotransformation of drugs. Enzyme induction is a process in which exposure to specific substrates (eg, drugs, environmental pollutants) causes accelerated biotransformation with a corresponding reduction in unmetabolized drug. Most drugs may have reduced efficacy due to rapid metabolism, but drugs with active metabolites may have increased pharmacologic effect and/or toxicity due to enzyme induction. Enzyme inhibition occurs when 2 drugs that share metabolism through the same isoenzyme compete for the same enzyme receptor site. The more potent inhibitor will dominate, resulting in decreased metabolism of the competing drug. For most drugs, this can lead to an increased level of unmetabolized unit in serum, leading to greater potential for toxicity. For drugs whose pharmacological activity requires biotransformation of a prodrug form, inhibition may lead to reduced efficacy.
Factors that contribute to patient-to-patient variability in biotransformation include genetic polymorphism, disease, age, and sex. The two isoenzymes most affected by genetic control are CYP2C19 and CYP2D6 (4). People who lack the gene for these isoenzymes metabolize poorly; those who have it are able to metabolize normal drugs and are considered extensive metabolizers (1). Medical conditions that affect metabolism include liver disease, which affects organ function, and congestive heart failure, which causes reduced blood flow to the liver. The aging process affects the cytochrome P450 monooxygenase system more than any other metabolic pathway.3). Reduced biotransformation occurs in newborns due to underdevelopment of the microsomal components of the liver.5). In the elderly, reductions in hepatic blood flow, enzyme activity, and liver weight result in decreased metabolic activity.
CYP3A4 ISOZYME INTERACTIONS
Research on the CYP3A4 isoenzyme and drug-drug/drug-food interactions is becoming an integral part of drug research. Recent reports of serious and sometimes fatal reactions to concomitant administration of certain drugs warrant careful consideration. Prescribing drugs to patients on multidrug regimens requires a complete review of the patient's current therapy in terms of drug biotransformation.
For drugs metabolized by CYP3A4 that require periodic monitoring of serum concentrations, the interaction of another drug metabolized by CYP3A4 can be controlled by adjusting the dosage to maintain the monitored drug concentration. Cyclosporine (CYA), tacrolimus and carbamazepine are CYP3A4 substrates. Co-administration of cyclosporine with a CYP3A4 inhibitor reduces the individual requirement for CYA. Drinking grapefruit juice may be an inexpensive way to reduce cyclosporine doses, but the unpredictable nature of CYA metabolism inhibition does not support this practice. Ketoconazole and diltiazem, the purest CYP3A4 inhibitors, have been used successfully in this regard. Patients who are unable to achieve therapeutic concentrations of CYA with oral cyclosporine due to insufficient absorption can be given either of these agents to achieve this goal.
The real problem with prescribing drugs that share the CYP3A4 pathway is with drugs whose concentrations are not measured. Once serum levels of these drugs reach a toxic state, the toxicity can manifest itself with serious medical consequences. The proarrhythmic effects of high serum concentrations of non-sedating antihistamines such as terfenadine and astemizole have severely limited their usefulness and have led to the development of new agents to replace them. Mibefradil (Posicor), a potent CYP3A4 inhibitor, was withdrawn from the market following numerous reports of serious drug interactions.
Another notable class of drugs in this category are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. High serum concentrations of some of these factors are strongly associated with the development of rhabdomyolysis. The addition of a CYP3A4 inhibitor to a regimen that includes certain HMG-CoA reductase inhibitors significantly increases the patient's risk of developing rhabdomyolysis. One of the advantages of recognizing this drug interaction was subsequent research to determine which agents could be used safely in multi-drug combinations. Studies focusing on CYP3A4 inhibitors and HMG-CoA reductase inhibitors have shown that pravastatin and fluvastatin can be co-administered with itraconazole, a strong CYP3A4 inhibitor, without significant changes in peak serum concentrations (6,7).
APPLICATION
OTablewas provided to identify drugs that share the CYP3A4 isoenzyme. Some drugs are metabolized by more than one isoenzyme and, as they have a dual metabolic pathway, their use cannot be ruled out after a risk-benefit analysis. Additional research on cytochrome P450 metabolism will continue to provide clinicians with guidance on the appropriate agents to use when circumstances arise that warrant the use of multi-drug regimens.
Table
Cytochrome P450 drug metabolism*
Open in a separate window
Confirmation
Special thanks to Dr. Carlos E. Velasco for assistance in preparing this manuscript.
Bibliography
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6.Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin, but not pravastatin, is highly susceptible to interactions with the CYP3A4 inhibitor itraconazole.Clin Pharmacol Ther.1998;63:332–341.[PubMed][Google Scholar]
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FAQs
Drug interactions caused by cytochrome P450? ›
Drug interactions involving the P450 isoforms generally are of two types: enzyme induction or enzyme inhibition. Common substrates, inhibitors and inducers of P450 isozymes. Enzyme inhibition reduces metabolism, whereas induction can increase it.
What may happen to drug interactions involving cytochrome P450 enzymes? ›Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures.
Which drug commonly interacts with the cytochrome P450 3a4 enzyme? ›Common drug-drug interactions involving CYP3A4 include: clarithromycin/erythromycin and simvastatin resulting in myopathy or rhabdomyolysis. diltiazem/verapamil and prednisone resulting in immunosuppression caused by increased prednisolone levels9.
Which drug binds to CYP450 system causing competitive inhibition? ›CYP450 metabolic pathways involved in the metabolism of clopidogrel and omeprazole, and their respective affinities are depicted. Competitive inhibition will be expected at CYP3A4 and mechanism-based inhibition at the CYP2C19 enzymatic level. Clopidogrel is the victim drug and omeprazole acts as the perpetrator drug.
What is the problem with cytochrome P450? ›The severe form of cytochrome P450 oxidoreductase deficiency is sometimes called Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis. Hormonal changes in affected males and females lead to the development of ambiguous genitalia or other genital abnormalities, as well as infertility.
Which of the following most likely results in cytochrome P450 inhibition? ›Acute alcohol use causes inhibition of the P450 system because the P450 enzymes are saturated by the toxic metabolites of acute ingestion.
What are CYP450 inducers and inhibitors? ›The cytochrome P450 (CYP450) enzymes are essential to produce numerous agents, including cholesterol and steroids. They are also necessary for the detoxification of foreign chemicals and the metabolism of drugs. Drugs that cause CYP450 drug interactions are referred to as either inhibitors or inducers.
Which of the following medications is most likely a P450 inducer? ›Commonly tested p450 inducers include phenytoin, griseofulvin, St. John's Wort, carbamazepine, rifampin, barbiturates, and chronic alcohol use.
What is an example of a metabolism drug interaction? ›Drug Metabolism
These interactions can cause increased or decreased drug exposures when two or more drugs are co-administered. For example, cytochrome P450 inhibition (CYP450) may increase the plasma levels of co-administered drugs leading to toxicity.
- Abiraterone.
- Adagrasib.
- Cinacalcet.
- Darifenacin.
- Darunavir.
- Duloxetine.
- Givosiran.
- Lorcaserin.
What drugs inhibit drug metabolizing enzymes? ›
| Enzyme | Inhibitor |
|---|---|
| CYP2B6 | clopidogrel(a), sertraline, thiotepa(a), ticlopidine(a) |
| CYP2C8 | gemfibrozil glucuronide(a), montelukast, phenelzine(a) |
| CYP2C9 | sulfaphenazole, tienilic acid(a) |
| CYP2C19 | N-3-benzyl-nirvanol, loratadine, nootkatone, ticlopidine(a) |
Enzyme induction increases metabolism of all drugs that are metabolized by that particular P450 isoenzyme. Therefore, when multiple drugs are given, drug interactions are likely at the level of P450 metabolism. This is the major mechanism for drug-drug interactions.
Is cytochrome P450 good or bad? ›The CYP450 enzymes are essential for the production of numerous agents including cholesterol and steroids. Additionally, these enzymes are necessary for the detoxification of foreign chemicals and the metabolism of drugs.
What is cytochrome P450 responsible for? ›Cytochrome P450 represents a family of isozymes responsible for biotransformation of many drugs via oxidation. The enzymes are heme-containing membrane proteins, which are located in the smooth endoplasmic reticulum of several tissues.
What are the symptoms of cytochrome P450? ›Signs and symptoms of mild cases can include a failure to begin menstruation by age 16 (primary amenorrhea), an inability to have biological children (infertility) in both men and women, and a condition called polycystic ovarian syndrome (PCOS).
What organ contains highest amounts of cytochrome P450? ›Cytochrome P450 (CYPs) enzymes are responsible for the metabolism of many exogenous and endogenous compounds. CYPs are abundant in the liver and are also expressed in many extra-hepatic tissues including the brain.
What is the organ where drugs are metabolized by cytochrome P450? ›As the primary site of drug metabolism, the liver functions to detoxify and facilitate excretion of xenobiotics (foreign drugs or chemicals) by enzymatically converting lipid-soluble compounds to more water-soluble compounds.
Is alcohol a CYP450 inducer or inhibitor? ›Ethanol is known to induce certain cytochrome P450 (CYP) enzymes, particularly the 2E1 isoform, which has been shown to metabolise arachidonic acid (AA) to the 19-hydroxy metabolite (19-HETE), which could have pro-hypertensive activity; CYP4A, by comparison, is the principal AA omega-hydroxylase in the liver.
What foods can interfere with CYP metabolism of drugs? ›Foods consisting of complex chemical mixtures, such as fruits, alcoholic beverages, teas, and herbs, possess the ability to inhibit or induce the activity of drug-metabolizing enzymes.
What are P450 inducers examples? ›- Anticonvulsants: phenytoin, carbamazepine, phenobarbitone.
- Steroids: dexamethasone, prednisolone, glucocorticoids.
- Antibiotics: rifampicin, griseofulvin.
- Others: nicotine, alcohol, cigarette smoke, St John's Wort.
Is omeprazole a CYP450 inhibitor? ›
Abstract. Enzymes of the cytochrome P450 family play a key role in xenobiotic and thus drug metabolism. The H+,K(+)-ATPase blocker, omeprazole, has been reported to inhibit (subfamily P450IIC) or induce (P450IA) this system.
Is grapefruit juice a P450 inducer? ›Grapefruit juice inhibits the CYP3A4 enzyme of the cytochrome P450 system in the intestinal mucosa, increasing the bioavailability of drugs with a high first pass metabolism.
What does P450 inducer mean? ›Enzyme induction and inhibition. Frequent administration of certain drugs leads to increased synthesis (transcription or translation), or induction, of P450 enzymes. Enzyme induction increases metabolism of all drugs that are metabolized by that particular P450 isoenzyme.
What are 3 common drug interactions? ›- Drug-drug interaction: A reaction between two (or more) drugs.
- Drug-food interaction: A reaction between a drug and a food or beverage.
- Drug-condition interaction: A reaction that occurs when taking a drug while having a certain medical condition.
An adverse drug reaction (ADR) is simply a bad side effect.
What are the four major types of drug interactions? ›- Another drug the person is taking (drug-drug interaction)
- Food, beverages, or supplements the person is consuming (drug-nutrient interaction)
- Another disease the person has (drug-disease interaction)
Diphenhydramine appears to cause mild inhibition of the cytochrome P450 (CYP) 2D6 enzyme. This can be interpreted as competitive inhibition, suggesting that diphenhydramine may be a CYP2D6 substrate.
What drugs should be avoided with CYP2D6 deficiency? ›- Codeine. Codeine may cause serious side effects (respiratory depression, confusion, lethargy) in these patients. ...
- Tramadol. Tramadol may cause serious side effects (respiratory depression, confusion, lethargy) in ultra-rapid metabolizers of CYP2D6. ...
- Amitriptyline. ...
- Paroxetine. ...
- Ondansetron.
Codeine should be avoided in CYP2D6 ultrarapid metabolizers because of the potential for toxicity.
What happens when a drug inhibits an enzyme? ›An enzyme inhibitor stops ("inhibits") this process, either by binding to the enzyme's active site (thus preventing the substrate itself from binding) or by binding to another site on the enzyme such that the enzyme's catalysis of the reaction is blocked. Enzyme inhibitors may bind reversibly or irreversibly.
What is the main organ that inactivates and metabolizes drugs? ›
Most drugs must pass through the liver, which is the primary site for drug metabolism. Once in the liver, enzymes convert prodrugs to active metabolites or convert active drugs to inactive forms. The liver's primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes.
What are common drug interactions? ›- Propranolol and asthma. Propranolol is a beta blocker medication used to treat conditions like high blood pressure. ...
- Diphenhydramine and glaucoma. ...
- Pseudoephedrine and high blood pressure. ...
- Furosemide and severe kidney disease. ...
- Acetaminophen and liver disease.
Inducers: carbamazepine, phenobarbital, rifampin, tobacco. Substrates: caffeine, clozapine, theophylline.
What are 3 mechanisms of drug drug interactions? ›Mechanisms of Drug Interactions I: Absorption, Metabolism, and Excretion.
What is the most common way drugs affect enzymes? ›The majority of drugs which act on enzymes act as inhibitors and most of these are competitive, in that they compete for binding with the enzyme's substrate- for example the majority of the original (first generation) kinase inhibitors bind to the ATP pocket of the enzyme.
What is the role of P450 enzymes and what role do they play in breaking down psychiatric medications? ›The best-known function of the cytochrome P450 enzymes is metabolism of drugs followed by the breakdown of toxic compounds including metabolic byproducts such as bilirubin which can lead to harmful results if not deactivated at a normal rate2.
What happens if repeated exposure to a drug increases the activity of the CYP450 enzyme? ›If repeated exposure to a drug increases the activity of the CYP450 enzyme that is responsible for metabolizing that drug, then later doses will be less effective than the first few doses.
What effect does CYP450 inhibitors or inducers have on oral contraceptives? ›Oral contraceptive hormones (OCs) are metabolized by the hepatic cytochrome p450 system; thus, inducers of the p450 system may increase OC metabolism.
What sort of reactions do cytochrome P450 enzymes Catalyse? ›Cytochrome P450 enzymes primarily catalyze mixed-function oxidation reactions, plus some reductions and rearrangements of oxygenated species, e.g. prostaglandins.
What drug should not be given to a patient that is a poor CYP2D6 metabolizer? ›Codeine should be avoided in CYP2D6 ultrarapid metabolizers because of the potential for toxicity.
What happens if two drugs are metabolised by the same enzyme? ›
Enzyme inhibition occurs when 2 drugs sharing metabolism via the same isozyme compete for the same enzyme receptor site. The more potent inhibitor will predominate, resulting in decreased metabolism of the competing drug.
How do you remember P450 inducers and inhibitors? ›Cytochrome P450 (CYP450) enzymes can be inhibited or induced by some drugs, resulting in significant drug interactions that can cause unanticipated adverse reactions or therapeutic failures. An easy way to remember the mnemonic is; CRAP GPs spend all day on SICKFACES.com.
What drugs are affected by enzyme inducers? ›- Antibiotics – rifampicin and rifabutin.
- Antiepileptics – carbamazepine, eslicarbazepine acetate, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide and topiramate (doses of 200mg daily or higher)
- Antiretrovirals – ritonavir, efavirenz and nevirapine.
The major consequences of enzyme induction are pharmacokinetic drug–drug interactions leading to a faster metabolic elimination of coadministered drugs by the induced enzyme. As a consequence, plasma concentrations may remain subtherapeutic resulting in loss of efficacy.