CYP3A4 and MDR Mediated Interactions in Drug Therapy

Multiple drug therapy is recommended in many disease states including AIDS, cancer, diabetes, and stroke. Therefore, drug-drug interactions can result in changes in pharmacological or toxicological response following concomitant administration of many therapeutic agents. It has become evident that two factors i.e. drug efflux pump- P-glycoprotein (MDR gene product) and metabolizing enzyme- CYP3A4 play major roles in this process. These two key proteins regulate all pharmacokinetic and pharmacodynamic interactions through the process of drug absorption, metabolism, disposition and elimination. Co-administration of two or more drugs can affect these processes due to altered functions of P-glycoprotein (P-gp) and CYP3A4 and consequently change clinical response and final outcome. After co-administration, some drugs may induce the activity of P-gp and/or CYP3A4 resulting in subtherapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. Conversely, inhibition(s) of P-gp and/or CYP3A4 can cause enhanced plasma concentration and therefore, drug toxicity. Overlapping substrate specificities to these proteins make it difficult to understand perplexing pharmacokinetic interactions with multidrug regimens. Inter-patient variability of drug response can occur due to change in genetic profiles, intake of food, herbal supplement, and recreational drugs. In this review, we have outlined several clinically important CYP and MDR-mediated drug-drug interactions of antiretroviral agents, antineoplastic agents, azole antifungals, statins, methadone, antibacterials, cardiovascular medicines, immune modulators, recreational drugs and herbal agents. Mechanisms by which such drug interactions occur have been briefly discussed in some of the examples.     

Drug interactions during therapy with three major groups of antimicrobial agents

This review focuses on drug–drug interactions with three major groups of antimicrobial agents: macrolides (including azalides and ketolides), quinolones, which are widely used for the treatment of bacterial infections, and azoles, which are used for antifungal therapy. Macrolides and the ketolide telithromycin are potent inhibitors of CYP3A4 and thus interfere with the pharmacokinetics of many other drugs that are metabolised by this enzyme. In contrast, although closely related, azithromycin is not a cytochrome inhibitor. All quinolones form complexes with di- and trivalent cations and, therefore, the absorption of quinolones can be dramatically reduced when given concomitantly with mineral antacids, zinc or iron preparations. Ciprofloxacin exhibits an inhibitory potential for the cytochrome isoenzyme 1A2, resulting in an inhibition of theophylline metabolism. Other quinolones, such as levofloxacin or moxifloxacin, do not interfere with theophylline metabolism. The systemic azoles, such as ketoconazole, itraconazole, fluconazole and voriconazole, are inhibitors of CYP isoenzymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates of the MDR-1 gene product, P-glycoprotein. These features are the basis for most of the interactions occurring during azole therapy (e.g., in severely ill patients in the hospital who are treated with multiple drugs).     

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

Cytochrome P450 (CYP) drug oxidases play a pivotal role in the elimination of antipsychotic agents, and therefore influence the toxicity and efficacy of these drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes with antipsychotic agents. In particular, aspects of CYP pharmacogenetics, and the processes of CYP induction and inhibition all influence in-vivo rates of drug elimination. Certain CYPs that mediate the oxidation of antipsychotic drugs exhibit genetic variants that may influence in-vivo activity. Thus, single nucleotide polymorphisms (SNPs) in CYP genes have been shown to encode enzymes that have decreased drug oxidation capacity. Additionally, psychopharmacotherapy has the potential for drug-drug inhibitory interactions involving CYPs, as well as drug-mediated CYP induction. Literature evidence supports a role for CYP1A2 in the clearance of the atypical antipsychotics clozapine and olanzapine; CYP1A2 is inducible by certain drugs and environmental chemicals. Recent studies have suggested that specific CYP1A2 variants possessing individual SNPs, and possibly also SNP combinations (haplotypes), in the 5'-regulatory regions may respond differently to inducing chemicals. CYP2D6 is an important catalyst of the oxidation of chlorpromazine, thioridazine, risperidone and haloperidol. Certain CYP2D6 allelic variants that encode enzymes with decreased drug oxidation capacity are more common in particular ethnic groups, which may lead to adverse effects with standard doses of psychoactive drugs. Thus, genotyping may be useful for dose optimization with certain psychoactive drugs that are substrates for CYP2D6. However, genotyping for inducible CYPs is unlikely to be sufficient to direct therapy with all antipsychotic agents. In-vivo CYP phenotyping with cocktails of drug substrates may assist at the commencement of therapy, but this approach could be complicated by pharmacokinetic interactions if applied when an antipsychotic drug regimen is ongoing.     

Genetic polymorphism of cytochrome P450 enzymes in Asian populations: focus on CYP2D6

Published studies demonstrate that significant ethnic differences can exist in the metabolism of some drugs. These differences are caused by cytochrome P450 polymorphisms and result in the potential for wide interpatient and interethnic variability in adverse events. One of the most common of these cytochrome P450 polymorphisms is related to the CYP2D6 isozyme. Many classes of commonly used drugs are metabolized by CYP2D6, creating the potential for significant adverse events. Due to the variety of genetic polymorphisms among Asian populations, this article focuses on this group rather than on other ethnic populations and discusses the clinical importance of genetic polymorphisms with regard to potential drug interactions. Polymorphism of CYP2D6 can either increase the rate of drug elimination (ultrametabolizers, leading to faster metabolic clearance potentially resulting in reduced effectiveness and need for higher doses) or decrease drug metabolism (poor metabolizers, which may increase the potential for drug interactions and adverse events). Although the CYP2D6 poor metabolizer phenotype is less frequent in Asian than in Western populations (e.g. about 1% in Thai, Chinese and Japanese populations and up to 4.8% in Indians versus 5-10% in Caucasians), the increased prevalence of the CYP2D6*10 allele in Asians does have an impact on drugs metabolized by CYP2D6. Enzyme activity is reduced, potentially increasing circulating drug doses and increasing the risk for drug interactions. Thus, in Asian populations it may be important to optimize pharmacotherapy either by assessing patients' CYP2D6 genotype, or by prescribing medications that are not metabolized by this isozyme.     

Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach

Observational studies have documented that women take a variety of medications during pregnancy. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs. The use of mechanistic-based approaches to drug interactions has significantly increased our ability to predict clinically significant drug interactions and improve clinical care. This same method can also be used to improve our understanding regarding the effect of pregnancy on pharmacokinetics of drugs. Limited studies suggest bioavailability of drugs is not altered during pregnancy. Increased plasma volume and protein binding changes can alter the apparent volume of distribution (Vd) of drugs. Through changes in Vd and clearance, pregnancy can cause increases or decreases in the terminal elimination half-life of drugs. Depending on whether a drug is excreted unchanged by the kidneys or which metabolic isoenzyme is involved in the metabolism of a drug can determine whether or not a change in dosage is needed during pregnancy. The renal excretion of unchanged drugs is increased during pregnancy. The metabolism of drugs catalysed by select cytochrome P450 (CYP) isoenzymes (i.e. CYP3A4, CYP2D6 and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes (i.e. UGT1A4 and UGT2B7) are increased during pregnancy. Dosages of drugs predominantly metabolised by these isoenzymes or excreted by the kidneys unchanged may need to be increased during pregnancy in order to avoid loss of efficacy. In contrast, CYP1A2 and CYP2C19 activity is decreased during pregnancy, suggesting that dosage reductions may be needed to minimise potential toxicity of their substrates. There are limitations to the available data. This analysis is based primarily on observational studies, many including small numbers of women. For some isoenzymes, the effect of pregnancy on only one drug has been evaluated. The full-time course of pharmacokinetic changes during pregnancy is often not studied. The effect of pregnancy on transport proteins is unknown. Drugs eliminated by non-CYP or non-UGT pathways or multiple pathways will need to be evaluated individually. In conclusion, by evaluating the pharmacokinetic data of a variety of drugs during pregnancy and using a mechanistic-based approach, we can start to predict the effect of pregnancy for a large number of clinically used drugs. However, because of the limitations, more clinical, evidence-based studies are needed to fully elucidate the effects of pregnancy on the pharmacokinetics of drugs.     

Computational models for predicting interactions with cytochrome p450 enzyme

Cytochrome p450 (CYP) enzymes are predominantly involved in Phase 1 metabolism of xenobiotics. As only 6 isoenzymes are responsible for approximately 90 % of known oxidative drug metabolism, a number of frequently prescribed drugs share the CYP-mediated metabolic pathways. Competing for a single enzyme by the co-administered therapeutic agents can substantially alter the plasma concentration and clearance of the agents. Furthermore, many drugs are known to inhibit certain p450 enzymes which they are not substrates for. Because some drug-drug interactions could cause serious adverse events leading to a costly failure of drug development, early detection of potential drug-drug interactions is highly desirable. The ultimate goal is to be able to predict the CYP specificity and the interactions for a novel compound from its chemical structure. Current computational modeling approaches, such as two-dimensional and three-dimensional quantitative structure-activity relationship (QSAR), pharmacophore mapping and machine learning methods have resulted in statistically valid predictions. Homology models have been often combined with 3D-QSAR models to impose additional steric restrictions and/or to identify the interaction site on the proteins. This article summarizes the available models, methods, and key findings for CYP1A2, 2A6, 2C9, 2D6 and 3A4 isoenzymes.     

Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition

Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.     

Efflux transporters and their clinical relevance

It is increasingly recognized that efflux transporters play an important role, not only in chemo protection e.g. multi-drug resistance, but also in the absorption, distribution, and elimination of drugs. The modulation of drug transporters through inhibition or induction can lead to significant drug-drug interactions by affecting intestinal absorption, renal secretion, and biliary excretion, thereby changing the systemic or target tissue exposure of the drug. Few clinically significant drug interactions that affect efficacy and safety are due to a single mechanism and there is considerable overlap of substrates, inhibitors, and inducers of efflux transporters and drug metabolizing enzymes, such as CYP3A. As well, genetic polymorphisms of efflux transporters have been correlated with human disease and variability of drug exposure. Accordingly, this review will discuss drug interactions and suitable probe substrates, as well as, the clinical relevance of the variability and modulation of efflux transporters and the exploitation of substrates as diagnostic tools. An update is given on inhibitors, which clinically reverse drug resistance and minimize the risk of metabolic interactions.     

Practical perspectives on the use of tipranavir in combination with other medications: lessons learned from pharmacokinetic studies

Drug-drug interactions are a major practical concern for physicians treating human immunodeficiency virus (HIV) because of the many medications that HIV-positive patients must take. Pharmacokinetic drug interactions can occur at different levels (absorption, distribution, metabolism, excretion) and are difficult to predict. Of all the processes that give rise to drug interactions, metabolism by cytochrome P450 (CYP3A) is the most frequent. Moreover, medications prescribed to HIV-positive patients may also be CYP3A inhibitors and inducers: Tipranavir, in the absence of ritonavir, is a CYP3A inducer, and ritonavir is a CYP3A inhibitor. Fortunately, the drug interactions between tipranavir coadministered with ritonavir and other antiretroviral medications or with other medications commonly used in HIV therapy are well characterized. This review summarizes the pharmacokinetic interactions between tipranavir/ritonavir and 11 other antiretroviral medications and between tipranavir/ritonavir and drugs used to treat opportunistic infections such as fungal infections, antiretroviral-treatment-related conditions such as hyperlipidemia, and side effects such as diarrhea.     

Drug interactions during therapy with three major groups of antimicrobial agents

This review focuses on drug-drug interactions with three major groups of antimicrobial agents: macrolides (including azalides and ketolides), quinolones, which are widely used for the treatment of bacterial infections, and azoles, which are used for antifungal therapy. Macrolides and the ketolide telithromycin are potent inhibitors of CYP3A4 and thus interfere with the pharmacokinetics of many other drugs that are metabolised by this enzyme. In contrast, although closely related, azithromycin is not a cytochrome inhibitor. All quinolones form complexes with di- and trivalent cations and, therefore, the absorption of quinolones can be dramatically reduced when given concomitantly with mineral antacids, zinc or iron preparations. Ciprofloxacin exhibits an inhibitory potential for the cytochrome isoenzyme 1A2, resulting in an inhibition of theophylline metabolism. Other quinolones, such as levofloxacin or moxifloxacin, do not interfere with theophylline metabolism. The systemic azoles, such as ketoconazole, itraconazole, fluconazole and voriconazole, are inhibitors of CYP isoenzymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates of the MDR-1 gene product, P-glycoprotein. These features are the basis for most of the interactions occurring during azole therapy (e.g., in severely ill patients in the hospital who are treated with multiple drugs).     

Pharmacokinetic herb-drug interactions: are preventive screenings necessary and appropriate?

Pharmacokinetic interactions often occur as a result of activity changes of drug-metabolizing and transporting proteins, especially cytochrome P450 (CYP) isoenzymes and P-glycoprotein (P-gp). The activity of these enzymes and drug transporters can be enhanced or inhibited by synthetic drugs as well as by natural products. Since the number of herb-drug interactions has increased in recent years, systematic in vitro screenings and more clinical studies to identify such interactions were proposed for herbal medicinal products. However, previous results regarding this issue are not only contradictory but also of less predictability. One reason for the discrepancies could be the lack of validation of the recommended in vitro tests. Furthermore, it has to be considered that pharmacokinetic drug interactions are not only mediated by herbal medicines but also by several foods, beverages and life-style products. Since herbal medicines are considered to have a broad therapeutic range, a preventive risk assessment for pharmacokinetic drug interactions should first be realized for synthetic drugs with a narrow therapeutic index. Efforts to identify all possible interactions will lead to limitless investigations and to inconsistent decisions.     

A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice

CYP3A is one of the most important drug-metabolizing enzymes, determining the first-pass metabolism, oral bioavailability, and elimination of many drugs. It is also an important determinant of variable drug exposure and is involved in many drug-drug interactions. Recent studies with CYP3A knockout and transgenic mice have yielded a number of key insights that are important to consider during drug discovery and development. For instance, studies with tissue-specific CYP3A-transgenic mice have highlighted the importance of intestinal CYP3A-dependent metabolism. They also revealed that intestinal CYP3A plays an important role in the regulation of various drug-handling systems in the liver. Intestinal CYP3A activity can thus have far-reaching pharmacological effects. Besides CYP3A, the active drug efflux transporter P-glycoprotein also has a strong effect on the pharmacokinetics of numerous drugs. CYP3A and P-glycoprotein have an extensive overlap in their substrate spectrum. It has been hypothesized that for many drugs, the combined activity of CYP3A and P-glycoprotein makes for efficient intestinal first-pass metabolism of orally administered drugs as a result of a potentially synergistic collaboration. However, there is only limited in vitro and in vivo evidence for this hypothesis. There has also been some confusion in the field about what synergy actually means in this case. Our recent studies with Cyp3a/P-glycoprotein combination knockout mice have provided further insights into the CYP3A-P-glycoprotein interplay. We here present our view of the status of the synergy hypothesis and an attempt to clarify the existing confusion about synergy. We hope that this will facilitate further critical testing of the hypothesis and improve communication among researchers. Above all, the recent findings and insights into the interplay between CYP3A and P-glycoprotein may have implications for improving oral drug bioavailability and reducing adverse side effects.     

Cytochrome P450-mediated cardiovascular drug interactions

INTRODUCTION: There are numerous drug-drug interactions (DDIs) related to cardiovascular medications and many of these are mediated via the cytochrome P450 (CYP) system. Some of these may lead to serious adverse events and it is, therefore, essential that clinicians are aware of the important interactions that occur. AREAS COVERED: An extensive literature search was performed to analyze the CYP-mediated cardiovascular DDIs that lead to a loss of efficacy or potential toxicity. Cardiovascular drugs may be victims or act as perpetrators of DDIs. The paper analyzes CYP-mediated drug interactions concerning anticoagulants, antiplatelet agents, antiarrhythmics, β-blockers, calcium antagonists, antihypertensive medications, lipid-lowering drugs and oral antidiabetic agents. EXPERT OPINION: Cardiovascular DDIs involving the CYP system are numerous. Additionally, the spectrum of drugs prescribed is constantly changing, particularly with cardiovascular diseases and it is not necessarily the case that drugs that had shown safety earlier will always show safety. Clinicians are encouraged to develop their knowledge of CYP-mediated DDIs so that they can choose safe drug combination regimens, adjust drug dosages appropriately and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.     

氟西汀的药代动力学及其与CYP450酶的作用

氟西汀是近年来开发的一种新型 5 羟色胺重摄取抑制剂 ,它通过选择性抑制突触间 5 羟色胺 (5 HT)的重摄取和代谢 ,增加突触间 5 HT的传递而发挥作用。氟西汀由细胞色素P45 0 (CYP45 0 )酶进行氧化代谢 ,现已证明CYP2C9,CYP2C19和CYP2D6是介导氟西汀N 去甲基代谢的主要CYP45 0同工酶。由于氟西汀及代谢产物去甲氟西汀分别为CYP2D6、CYP3A4、CYP2C19和CYP2C9的抑制剂 ,因此它可与经这些CYP同工酶催化代谢的药物产生明显的相互作用 ;从而导致不同个体间的药代动力学差异和疗效差异。     

Safety and potential of drug interactions of caspofungin and voriconazole in multimorbid patients

Due to their broad antimycotic spectrum and the relatively low rate of side effects, the two antifungals caspofungin and voriconazole are considered as attractive therapeutic alternatives to amphotericin B. However, treatment of severe mycotic infections in patients taking co-medication is associated with the risk of severe adverse drug interactions. The risk of such interactions is increased if voriconazole and, much less pronounced caspofungin, are co-administered with drugs which have an inducing or inhibiting effect on the CYP 450 system, primarily on the isoenzymes CYP2C19, CYP2C9 and CYP3A4. This review provides a comprehensive overview on the potential drug interactions of caspofungin and voriconazole in multimorbid patients.     

The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.     

Antiarrhythmics: elimination and dosage considerations in hepatic impairment

Many drugs, including most antiarrhythmics (some of which are now of limited clinical use) are eliminated by the hepatic route. If liver function is impaired, it can be anticipated that hepatic clearance will be delayed, which can lead to more pronounced drug accumulation with multiple dosing. Consequently, the potential risks of adverse events could be increased, especially as antiarrhythmics have a narrow therapeutic index. The present review summarises the available pharmacokinetic data on the most popular antiarrhythmic drugs to identify the enzymes involved in the metabolism of the various agents and confirm whether liver disease affects their elimination. Despite long usage of some of these drugs (e.g. amiodarone, diltiazem, disopyramide, procainamide and quinidine), surprisingly few data are available in patients with liver disease, making it difficult to give recommendations for dosage adjustment. In contrast, for carvedilol, lidocaine (lignocaine), propafenone and verapamil, sufficient clinical studies have been performed. For these drugs, a marked decrease in systemic and/or oral clearance and significant prolongation of the elimination half-life have been documented, which should be counteracted by a 2- to 3-fold reduction of the dosage in patients with moderate to severe liver cirrhosis. For sotalol, disopyramide and procainamide, renal clearance contributes considerably to overall elimination, suggesting that dosage reductions are probably unnecessary in patients with liver disease as long as renal function is normal. The hepatically eliminated antiarrhythmics are metabolised mainly by different cytochrome P450 (CYP) isoenzymes (e.g. CYP3A4, CYP1A2, CYP2C9, CYP2D6) and partly also by conjugations. As the extent of impairment in clearance is in the same range for all of these agents, it could be assumed that they have a common vulnerability and that, consequently, hepatic dysfunction will affect CYP-mediated phase I pathways in a similar fashion. The severity of liver disease has been estimated clinically by the validated Pugh score, and functionally by calculation of the clearance of probe drugs (e.g. antipyrine). Both approaches can be helpful in estimating/predicting impairments in drug metabolism, including antiarrhythmics. In conclusion, hepatic impairment decreases the elimination of many antiarrhythmics to such an extent that dosage reductions are highly recommended in such populations, especially in patients with cirrhosis.     

CYP2C9和CYP2C19基因多态性对药物代谢的影响及个体化用药研究进展

CYP2C9、CYP2C19酶是细胞色素P450系统中重要的药物代谢酶,共同参与许多重要药物的体内代谢。CYP2C9、CYP2C19基因具有高度多态性,在基因编码区和非编码区存在许多碱基突变,这种突变会影响酶的活性,导致酶底物药物清除率改变,从而导致药品不良反应的发生。本文对CYP2C9、CYP2C19基因突变的发生频率及对药物代谢的影响做详细阐述。