Changes In Drug Metabolism Research Articles

Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy

The purpose of this study was to determine whether drug metabolism (CYP1A2, CYP2D6 and CYP3A) activity varies in the pregnant state compared with the nonpregnant state. Subjects were studied at 14 to18 weeks of gestation, 24 to 28 weeks of gestation, and 36 to 40 weeks of gestation and again at 6 to 8 weeks after the delivery. Twenty-five subjects completed all 4 study periods and had evaluable data. Salivary caffeine clearance was used as a measure of CYP1A2 activity; dextromethorphan O- and N-demethylation were used to assess CYP2D6 and CYP3A activity, respectively. CYP1A2 activity was significantly reduced at all periods of the pregnancy as compared with the postpartum period during the first (-32.8% +/- 22.8%), second (-48.1% +/- 27%), and third periods (-65.2% +/- 15.3%), respectively. In contrast, CYP2D6 activity was increased significantly throughout the pregnancy (25.6% +/- 58.3% at 14-18 weeks of gestation, 34.8% +/- 41.4% at 24-28 weeks of gestation, and 47.8% +/- 24.7% at 36-40 weeks of gestation) as compared with the postpartum period. CYP3A activity was consistently, significantly increased (35%-38%) during all stages of the pregnancy. Opposing changes in drug metabolism occur during pregnancy, with CYP1A2 activity decreased and CYP2D6 and CYP3A activities increased. The direction of dosing adjustments during pregnancy will depend on the drug and the enzyme that is responsible for its metabolism.

Gastroesophageal Reflux in the Preterm Neonate

After completing this article, readers should be able to: 1. Describe the epidemiology and pathophysiology of gastroesophageal reflux (GER) in preterm neonates. 2. Delineate the associations of GER with apnea, chronic lung disease, behavior, and growth of preterm infants. 3. Review the investigations used to evaluate GER in preterm infants. 4. Describe nonpharmacologic and pharmacologic therapies for GER. Gastroesophageal reflux (GER) is a normal physiologic event occurring across the age spectrum. It may contribute to a variety of disorders, including esophagitis, feeding problems, and airway disease in all age groups. (1) A large number of symptoms and signs have been purported to be caused by GER despite a lack of data showing a clear association between a specific symptom and GER. In preterm infants, empiric therapy often is administered using agents of unproven efficacy and safety to treat symptoms that likely are unrelated to GER. In a survey on management practices for GER in preterm infants, common treatment strategies included positioning (98%) and slopes (96%), histamine 2 (H 2) receptor antagonists (100%), feed thickeners (98%), antacids (96%), prokinetics (79%), proton pump inhibitors (PPIs) (65%), and dopamine receptor antagonists (53%). (2)(3) The safety, efficacy, and appropriate dosing recommendations for most medical therapies remain uncertain in neonates. In this review, we attempt to summarize the current literature regarding physiology, pathophysiology, and diagnostic and management strategies for GER pertinent to the neonate, with an emphasis on the preterm infant. GER describes the retrograde movement of stomach contents (air or feeding, liquid or semisolid, acid or alkaline, enzymes or bile salts) into the esophagus. GER disease (GERD) occurs when GER causes symptoms or signs such as pain, poor weight gain, esophagitis, hematemesis, and airway symptoms, including apnea, aspiration, recurrent pneumonia, chronic lung disease (CLD), or large airway inflammation. However, any of these symptoms or signs …

Drug metabolism and ageing.

Important changes in drug metabolism occur with ageing. Age-associated reductions in function of some but not all cytochrome P450 enzymes (CYPs) have been described. Induction and inhibition of CYPs needs to be revisited in light of recent advances. The function and pharmacology of transporters have not yet been examined for an age-related effect. Finally, the concept of frailty is being underpinned by studies documenting a decline in drug metabolism and changes in disposition in frail older people compared with either healthy elderly or the young.

Chemotherapy in the elderly

Persons over the age of 65 years are the fastest growing segment of the US population. In the next 30 years it will comprise over 20% of the population. More than 50% of all cancers occur in this age group and therefore, the total cancer burden is expected to rise. Data are becoming available that will better guide the use of chemotherapy in the older patient population. Understanding the physiologic and functional changes that occur with aging will assist in developing useful strategies in the elderly. Pharmacokinetic data on a broad spectrum of chemotherapeutic agents will be presented. Many of these agents seem to have a beneficial therapeutic index, particularly in older patients. There has also been an increasing trend toward the use of oral chemotherapy. Factors that must be considered in choosing chemotherapy include limitations of saturability of absorption, patient compliance, and the pharmacokinetic and pharmacodynamic changes that occur in older patients. Interpatient variability and age-related changes in drug metabolism are discussed. Careful attention to the physiologic changes with age and dose adjustments necessary for end organ dysfunction (renal, hepatic) are needed to ensure the safe administration of chemotherapy to older patients.

Progress in clinical pharmacology over the last 20 years.

Progress in clinical pharmacology over the last 20 years.

Pharmacological factors influencing anticancer drug selection in the elderly.

Persons over the age of 65 years are the fastest growing segment of the US population. In the next 30 years this segment will represent more than 20% of the population. Fifty percent of all cancers occur in this age group and therefore the total cancer burden is expected to rise. Data are becoming available that will better guide the use of chemotherapy in the older patient population. Studies are presented discussing pharmacokinetic data on a number of chemotherapeutic agents with an emphasis on those that have entered clinical practice over the past few years. Many of these agents seem to have a beneficial therapeutic index, particularly in regard to older patients. Aging can affect the pharmacokinetics of chemotherapy in a number of ways. Absorption is only modified minimally by age. The greater concern with the use of oral drugs is patient compliance. Volume of distribution is affected by changes in body composition, anaemia and decreased plasma albumin concentration. There are many drugs in which renal excretion plays an important role. Decline in glomerular filtration is a consistent phenomenon with aging. Drug metabolism is primarily affected by changes in the P450 system and coadministration of drugs which also interact with this important enzyme system. The selection of chemotherapy in the elderly is frequently determined by degree of comorbidity and the patients' functional status. These factors are critical and can often determine response and toxicity. This article discusses the changes that occur with antimetabolites, camptothecins, anthracyclines, taxanes, platinum compounds, epipodophyllotoxins and vinca alkaloids. There has also been an increasing trend toward the use of oral chemotherapy. Factors that must be considered in selecting chemotherapeutic agents include limitations of saturability of absorption, patient compliance and the pharmacokinetic and pharmacodynamic changes that occur in older patients. Interpatient variability and age-related changes in drug metabolism are discussed. Careful attention to the physiological changes with age and dose adjustments necessary for end-organ dysfunction (renal, hepatic) are needed to ensure the safe administration of chemotherapy. In this article specific diseases are discussed (breast, colon, ovarian and non-small lung cancers) with recommendations for drug selection in adjuvant chemotherapy and the treatment of metastatic disease. Future studies will need to incorporate these various factors to properly evaluate chemotherapy in older patients. Research and educational initiatives targeted to this population will need to be a priority.

Pain management in the elderly.

Pain in the elderly is often unrecognized and undertreated. Ineffective pain management can have a significant impact on the quality of life of older adults, leading to depression, social isolation, and a loss of function. Proper assessment of older adults requires the physician to regularly ask about the presence of pain and be skillful in assessment strategies to evaluate the frequency and intensity of pain. Assessment of pain in older adults with dementia and communication disorders is especially challenging. Effective pain management in elderly patients should include both pharmacologic and nonpharmacologic strategies. Pharmacologic strategies call for administration of nonopioid analgesics, opioid analgesics, and adjuvant medication. Polypharmacy, drug-drug and drug-disease interactions, age-associated changes in drug metabolism, and the high frequency of adverse drug reactions need to be carefully considered in using medications in this population. Nonpharmacologic approaches such as cognitive-behavioral therapy, education, osteopathic manipulative treatment, and exercise should be applied in addition to pharmacologic therapy. Using a team approach and incorporating principles of pain management can effectively provide good analgesia for older adults.

Alcohol use and HIV pharmacotherapy.

Alcohol consumption by individuals infected with HIV is an important medical management issue with significant implications for the effectiveness of antiretroviral therapy as well as an important evolving field of HIV research. Alcohol consumption is a risk factor for poor medication adherence and can modify liver drug metabolism, both of which can lead to the emergence of drug-resistant virus. Research indicates that alcohol consumption greater than 50 g/day (four or five drinks) is a risk factor for liver disease progression among patients with HIV/HCV coinfection. In addition, alcohol-induced cirrhosis can result in changes in drug metabolism in the liver through compromised liver function. More research studies are needed to elucidate the biological and molecular basis of the clinical changes induced by alcohol consumption in HIV-infected individuals and on the relationship of these changes to the effectiveness of HIV pharmacotherapy. Specifically, research areas that are of particular importance are (1) determining alcohol consumption levels and patterns and its impact on antiretroviral medication adherence, efficacy, and physician prescribing practices; (2) identifying behavioral interventions to enhance adherence to HIV medications and reduce alcohol consumption; (3) clarifying the relationships and interactions among alcohol metabolism, HIV drug metabolism, and pharmacogenetics; (4) elucidating the extent of liver toxicity due to antiretroviral therapy and drug-drug interactions in individuals who consume alcohol; and (5) delineating the contribution of alcohol consumption to end-stage organ damage, particularly in HIV/HCV coinfection.

Clinical Relevance of Cytokine‐Induced Changes in Drug Metabolism

Cytokines are a group of potent peptides that regulate the immune response to a wide variety of stimuli including microbial agents, antigens and traumatic insult. In acute diseases involving a strong immune or inflammatory response, the metabolism of certain drugs is inhibited leading to increased and potentially toxic plasma concentrations. Investigations using hepatocytes and laboratory animals lend weight to the hypothesis that cytokines can regulate the level or activity of drug metabolising enzymes, in particular hepatic cytochrome P450 isoforms. Although these experimental tools may not precisely reflect the situation in human disease, it is apparent that cytokines can influence drug metabolism in many conditions involving an immunological component. Since cytokines are becoming increasingly used as therapeutic agents, or as targets for therapeutic intervention, their influence on drug metabolism will become clearer. In parallel with this increased understanding of the relationship between cytokines and drug metabolism, there will be an increased potential for cytokinedrug interactions.

Pharmacokinetic considerations of oral chemotherapy in elderly patients with cancer.

Persons over the age of 65 years are the fastest growing segment of the US population. In the next 30 years they will comprise over 20% of the population. Fifty per cent of all cancers occur in this age group and therefore there will be an expected rise in the total cancer burden. There has been an increasing trend over the past 20 years toward the use of oral chemotherapy. This change has been encouraged by the need to decrease the costs of chemotherapy administration, patient preferences and quality of life issues. Factors that must be considered with oral chemotherapy administration include limitations of saturability of absorption, patient compliance and pharmacokinetic/pharmacodynamic changes which occur in elderly patients. Interpatient variability and drug metabolism, particularly age-related changes in drug metabolism are being studied. The cytochrome P450 system has been intensively studied because of its importance with regard to chemotherapeutic drugs. This article reviews these issues and provides details regarding specific drugs including temozolomide, thalidomide, topotecan, the fluoropyrimidines, etoposide, hydroxycarbamide (hydroxyurea), tamoxifen, and alkylating drugs. Complementary and alternative therapies are also discussed.

HIV and drug allergy

Drug-related rashes have been estimated to be 100 times more common in HIV-positive patients than in the general population. The reasons for this are not clear, but are likely to be multifactorial, and include changes in drug metabolism, oxidative stress, cytokine profiles and immune hyperactivation. HIV itself may also serve as a danger signal, leading to the development of an immune response rather than tolerance. Drugs that are implicated in causing hypersensitivity have changed since the advent of highly active antiretroviral therapy. This is largely as a result of a decrease in the use of antimicrobials such as co-trimoxazole, and the introduction of new drugs of different classes, including abacavir, non-nucleoside reverse transcriptase inhibitors such as nevirapine, and protease inhibitors such as amprenavir. Laboratory evidence supporting a role of the immune system in the mechanism of co-trimoxazole hypersensitivity is available. However, this is not the case for the newer antiretrovirals; hypersensitivity to these agents is presumed to be immune-mediated based only on the symptomatology. It is essential that research be carried out into the mechanisms of hypersensitivity reactions associated with these important new classes of drugs so that their benefit-risk ratio can be improved, and lessons learned for future drug development.

HIV and drug allergy.

Drug-related rashes have been estimated to be 100 times more common in HIV-positive patients than in the general population. The reasons for this are not clear, but are likely to be multifactorial, and include changes in drug metabolism, oxidative stress, cytokine profiles and immune hyperactivation. HIV itself may also serve as a danger signal, leading to the development of an immune response rather than tolerance. Drugs that are implicated in causing hypersensitivity have changed since the advent of highly active antiretroviral therapy. This is largely as a result of a decrease in the use of antimicrobials such as co-trimoxazole, and the introduction of new drugs of different classes, including abacavir, non-nucleoside reverse transcriptase inhibitors such as nevirapine, and protease inhibitors such as amprenavir. Laboratory evidence supporting a role of the immune system in the mechanism of co-trimoxazole hypersensitivity is available. However, this is not the case for the newer antiretrovirals; hypersensitivity to these agents is presumed to be immune-mediated based only on the symptomatology. It is essential that research be carried out into the mechanisms of hypersensitivity reactions associated with these important new classes of drugs so that their benefit-risk ratio can be improved, and lessons learned for future drug development.

Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distribution

Traditionally, drug-induced changes in cytochrome P450 isoenzyme activity, causing changes in drug metabolism and bioavailability, have been the main focus of drug interaction studies. Recent research, however, suggests that the drug transporters P-glycoprotein and organic anion transporting peptide (OATP), which can effect the efflux and influx of many classes of drugs, may contribute to drug interactions by mechanisms independent of oxidative metabolism. Experimental models designed to selectively probe the function of P-glycoprotein or OATP have demonstrated that changes in the activities of these transporters may have a significant effect on the bioavailability of clinically important drugs, leading to the potential for adverse drug interactions.

Concentrations of tamoxifen and its major metabolites in hormone responsive and resistant breast tumours.

Patients treated with tamoxifen (TAM) for primary breast cancer often manifest de novo or acquired resistance, possibly through changes in drug metabolism. Using solid-phase extraction methods and reversed-phase high-performance liquid chromatography separations, levels of TAM and metabolites 4-hydroxytamoxifen (4OH) and desmethyltamoxifen (DMT) have been measured in plasma and tumour tissue from breast cancer patients treated with TAM for at least 3 months. Patients were categorized into those with tumours responding to TAM and those showing de novo or acquired resistance. Levels of TAM, 4OH and DMT in both plasma and tissue samples were correlated with clinical response, length of treatment and patient weight. Interesting results included accumulation of 4OH in tumour tissues over time in all patients, with significance reached in the acquired resistance group. In addition, significantly lower levels of 4OH and DMT were found in plasma taken from responding patients after 3 months of treatment when compared to non-responding patients, and a small group of ER-poor patients showed significantly lower levels of all three species in plasma when compared to other patients. Whilst not explaining TAM resistance in all cases, these differences could account for the development of resistance to TAM treatment in certain subgroups of patients. © 2000 Cancer Research Campaign

Metabolic basis of drug interactions in the intensive care unit.

Drug interactions are a potentially hazardous consequence of drug therapy, particularly in the critically ill. Many drug interactions result from changes in drug metabolism. These interactions can result in either an increase in toxicity or a decrease in effect. The process of normal drug metabolism depends on the activity of individual metabolizing enzymes. The activity of these enzymes can be altered by many factors, and it is alterations in these enzymes that account for most drug interactions. This article reviews normal and abnormal drug metabolism and discusses how this knowledge can be used to predict and prevent potential drug interactions.

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.

Efficacy of venlafaxine in geriatric depression.

Geriatric patients with major depression present clinical challenges not encountered in younger individuals, including a greater incidence of medical comorbidity, higher rates of multiple medication use, changes in drug metabolism due to age or physical illness, and increased sensitivity to antidepressant side effects. Nevertheless, successful treatment of depressive disorders in the elderly improves mental and physical functioning, decreases morbidity and perhaps mortality, and enhances quality of life. Recent research indicates that newer antidepressants are effective for late life depression and safer for older individuals. Among newer antidepressants, venlafaxine has a pharmacological profile that makes it an attractive choice for geriatric patients. It has limited potential to interact with other medications because it only weakly inhibits the cytochrome P450 system and binds to plasma proteins at a low level. Dosing may have to be adjusted for patients with renal failure, but typically not for those with liver disease or other medical conditions. Data from three double-blind and four open clinical trials support the safety and efficacy of venlafaxine for geriatric depression. Patients may experience transient, generally tolerable side effects such as insomnia, nausea, agitation, or dry mouth early in treatment, but more serious problems such as falls or cardiac rhythm disturbances seem to be rare. Treatment emergent hypertension occurs in a small percentage of older patients, generally at doses above 150 mg/day. Finally, emerging data suggest that venlafaxine may be effective for conditions such as stroke, anxiety, and neuropathic pain that frequently accompany depressive disorders in the elderly.

Metabolism, Bioavailability, and Drug Interactions

This article presents clinically relevant drug interactions which may confront the geriatric psychiatrist. Changes in drug metabolism due to aging, higher medical comorbidity, and frequent polypharmacy all place the older patient at a greater risk of developing a drug-drug interaction. Clinicians must be aware of the potential for such interactions, but they should also be able to determine which of those possible interactions is appropriate for a particular patient. Drug interactions are included in this article based on frequency of the interaction, clinical severity, and frequency of contact with the drugs prescribed by the practicing clinician.

The Systemic Inflammatory Response to Cardiopulmonary Bypass

The Systemic Inflammatory Response to Cardiopulmonary Bypass

Role of viral infections in the induction of adverse drug reactions.

A spectrum of adverse drug reactions that are caused by the combined action of drugs and viruses has been described: ampicillin rash in acute infectious mononucleosis; Reye's syndrome; hypersensitivity reactions to sulphonamides in patients with HIV infection; drug-induced agranulocytosis; paracetamol (acetaminophen) hepatotoxicity; aspirin (acetylsalicyclic acid)-induced asthma; Epstein-Barr virus-associated lymphoma and methotrexate; and AIDS-related Kaposi's sarcoma and nitrite use. Changes in pharmacokinetics have been reported for: caffeine, sulfamethoxazole and fluconazole in patients with HIV infection; theophylline, following influenza and influenza vaccination; and recently, dipyrone metabolites in carriers of the hepatitis B virus. In addition increased drug- and drug metabolite-related toxicity has been observed in virally infected cells. Pathogenetic mechanisms for the interaction between drugs and viruses are varied, and include biological mechanisms (often immunological) and changes in drug metabolism. The combined effects of chemical and biological exposure provide a unique model for the study of disease induction.