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Pharmacodynamic Studies of Drug Drug Interactions

We limit our attention here to several models that attempt to describe adverse effects arising from drug-drug interactions, an increasingly important area in pharmaceutical toxicology. The models involved in these studies cover a wide spectrum of endpoints, including effects on the central nervous system, kidney, cardiovascular, as well as antimicrobial activities. We look briefly at the following distinctive types of pharmacodynamic models sigmoid Emax, isobolo-graphic, and response surface. In each case we briefly mention the purpose of the study and introduce the modeling approach without going into details of the outcome of the studies. The readers are encouraged to consult the original references for additional information. The sigmoid Emax model formed the basis for a number of subsequent pharmacodynamic analyses of drug-drug interactions. For instance, Mandema et al. 82 , used quantitative electroencephalographic effect measurements to study pharmacodynamic interactions among...

Use of Various Inhibitor Concentrations for the Prediction of Drug Drug Interactions

5.35.4.1 Metabolic Drug-Drug Interaction Risk Evaluation Figure 2 Qualitative zoning for the prediction of drug-drug interactions (AUC ratio) involving CYP inhibition using the j K ratio. The theoretical curve is based on eqn 14 where F - represents false-negative, T - true-negative, F + false-positive, and T+ true-positive predictions. (Reproduced with permission from Houston, J. B. Galetin, A. Drug Metab. Rev 2003, 35, 393-415.) Figure 2 Qualitative zoning for the prediction of drug-drug interactions (AUC ratio) involving CYP inhibition using the j K ratio. The theoretical curve is based on eqn 14 where F - represents false-negative, T - true-negative, F + false-positive, and T+ true-positive predictions. (Reproduced with permission from Houston, J. B. Galetin, A. Drug Metab. Rev 2003, 35, 393-415.) Figure 3 The graph shows 193 studies involving drug-drug interactions for CYP3A4 (filled circle), CYP2D6 (filled triangle), and CYP2C9 (filled square) substrates. Open symbols represent...

Importance of In Vitro Tools in Drug Interaction Studies

Drug interactions can be defined as the modification of the safety and efficacy profile of a medication following the coadministration of drugs, environmental pollutants, ingredients or additives present in the diet (see 5.35 Modeling and Simulation of Pharmacokinetic Aspects of Cytochrome P450-Based Metabolic Drug-Drug Interactions). Drug interactions are usually defined as being either of pharmacodynamic or of pharmacokinetic origin. These two aspects are closely linked and need to be studied together to evaluate both safety and efficacy in the clinic. Only the latter category, defined also as metabolism-based interactions (i.e., the alteration of the metabolic clearance of a drug by another coadministered drug) will be further detailed in this chapter. With the increasing prevalence of polypharmacy,51'52 these drug interactions have become more frequent,51'53'54 and can lead to serious side effects, e.g., Cerivastatin55 and increased morbidity and mortality.54 It is well recognized...

In Vitro Toxicological Models And Methods Commonly Used In Drug Discovery

Ligand binding assays for the hERG (human ether-a-go-go-related gene) potassium channel have been developed to identify compounds that may have inhibitory activity and potential cardiotoxicity, especially Torsade de Pointes (see Chapters 13, 16, 19, and 20). The ligands used include 3H astemizole 5 , 3H dofetilide 6 , or other small molecule hERG ligands 7 . Alternatively, functional ion efflux across the biological membrane can be assayed by the nonradioactive Rb+ flux assay 8 . Furthermore electrophysiological techniques such as high-throughput patch clamping has emerged as the whole-cell functional readout for predicting drug interaction potential with these membrane channels 9,10 .

Pharmacodynamics The Mechanisms of Drug Action

PD is the study of drug action on the biologic and physiologic processes of both cells and biologic systems. The targets of drug interaction are usually specific macromolecules that induce a physiologic or biochemical change DNA, RNA, or other macromolecules involved in cell division (e.g., microtubules) an enzyme found either intracellularly or in the plasma an ion channel protein or structural protein.4 Many newer drugs bind to receptors that normally bind an endogenous regulatory ligand (e.g., growth factors, neurotransmitters, hormones) and drug binding to this receptor alters its function and or its downstream signaling responses. Agonists are drugs that mimic the endogenous ligand for the receptor (e.g., opioids, granulocyte colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEPO). Antagonists are drugs that block the effects of the endogenous ligand (e.g., trastuzumab (Herceptin) monoclonal antibody against HER-2 neu flutamide, an androgen receptor...

Human liver S9 fraction

The liver S9 fractions contain both microsomal and cytosolic fractions. They regroup therefore the same metabolic enzyme profile (phase I and phase II enzymes including their cofactors) as hepatocytes with the exception of the membrane barrier and its transporters. Hence, S9 fractions offer a more complete representation of the metabolic profile compared with microsomes and cytosolic fractions.2 They are therefore of great potential interest for in vitro studies in drug metabolism and drug interaction. However, their low enzyme activities compared to microsomes limit their use for drug metabolism studies.

Use of recombinant enzymes

The microsomal environment, i.e., lipids, apoproteins, level of both cytochrome b5 and NADPH cytochrome CYP reductase, is different in the cDNA-expressed CYP system from the one in human liver microsomes. These differences can affect the turnover number (Vmax) for a given enzyme, although the affinity (Km) of CYP is quite comparable between recombinant enzymes and human liver microsomes (Table 5). A thorough literature search performed with the aid of a drug interaction database (Aurquest database66) can illustrate this aspect (Table 5).

Reversible inhibition

Transformations of the Michaelis-Menten equation (Table 2) are not only used for calculating Ki values but also for graphical depiction of the type of inhibition.28 These equations allow to predict the risk of drug interaction as a change in substrate exposure (AUC) in presence of an inhibitor (AUCi AUC) (Table 2).

Irreversible inhibition

In irreversible inactivation, the inhibitor first acts on the target enzyme before inhibition occurs. In many case, this involves conversion of the inhibitor into a chemically reactive intermediate that forms a covalent bond with the enzyme, inactivating it permanently. For CYP enzymes, irreversible inhibition can be noncovalent occurring through metabolite-intermediate complexes tightly bound to the iron of the heme prosthetic group (quasi-irreversible inhibition). Irreversible inactivation, whether it occurs through formation of covalent bonds or iron complexes, is the underlying mechanism of some high-magnitude drug interactions,16 e.g., CYP2D6 inactivation by paroxetine,81 CYP3A4 inactivation by diltiazem,82 erythromycin, or troleandomycin, CYP2C9 inactivation by tienilic acid,84 etc. It is crucial to distinguish time-dependent inhibition due to the reversible inhibitory effect of a metabolite formed during the incubation from the irreversible inactivation of the enzyme by a...

Discussion and Conclusion

These safety and efficacy aspects have been discussed in this chapter, trying to show how in vitro metabolism tools can better address, at very early stages, the nature and the importance of metabolites formed throughout species as well as the drug interactions risks. These two issues have been recognized by regulatory authorities as major and the studies to be undertaken have been defined quite precisely for development programs and registration purposes in recent draft guidelines on safety testing of metabolites and predictions of drug interactions. These new requirements will have to be discussed and integrated by research teams. But one has to keep in mind that getting a similar level of understanding in research projects on series of drugs will only be possible if one can further adapt the tools using new technologies and apply different and more global interpretation strategies. Screening programs have in a way broken down the important mechanisms involved in drug disposition...

Isolated Cerebral Microvessels

In 1975 Goldstein etal.21 reported isolation of metabolically active capillaries from rat brain, and this preparation was used for a number of studies on transport and metabolism, e.g., for hexoses20 and small ions.22 Since Na + -dependent glutamate uptake by the BBB could not be detected in vivo, but was observed in isolated brain microvessels, where the bathing medium mainly has access to the outer vessel surface, an abluminal location for this transport was proposed.54 The vessels were less suitable for studies of processes with high energy demand such as transcytosis, possibly because of the damage caused in vessel isolation and the resultant impairment in ATP production. Recent improvements in technique have led to more physiological preparations of isolated brain microvessels preserving normal polarized (apical-basal) function, and modern confocal imaging techniques using fluorescent substrates have allowed good resolution of real-time transport activity at the single vessel...

Activation and Targeting Through Physico Chemical Stimuli

Drug-drug interactions that are pH sensitive may also play a role in modulating drug release from pH-responsive delivery systems. DOX-loaded particles prepared by Kataoka et al. 38 , displayed a drug release that depended upon conjugation not only between drug and polymer molecules but also between the drug molecules themselves. It was found that some of the DOX encapsulated in polymeric micelles actually formed a dimer referred to as DOX DOX via the formation of an azomethine bond. Release was, in part, dependent on the type of DOX being released. DOX monomer was released preferentially in the initial release phase, whereas DOX DOX was found to play a role in the sustained release of the drug. DOX DOX also showed a Ph-dependent release. Under acidic conditions, the azomethine bond in DOX DOX may be cleaved to release additional DOX monomer. Thus, the formation of DOX DOX dimers via acid-labile bonds may play a role in the pH sensitivity of DOX-loaded polymeric micelles 38 .

The Pharmacokinetics and Pharmacodynamics of Drugs in Elderly Cachectic Cancer Patients

The older population includes the majority of cancer patients. In fact, increasing age is directly associated with increasing rates of cancer, corresponding to an 11-fold greater incidence in persons over the age of 65 vs those under 65 4 . Older persons, compared to younger populations, typically have more diseases, take more medications, experience more adverse effects and drug interactions, and have more variability in their nutritional status and underlying health status, all of which contribute to pharmacokinetic (drug absorption, distribution, metabolism, and excretion) and pharmacodynamic (the effect of a drug on its target site) differences 5 . Thus, in this scenario, the study of cancer cachexia in the geriatric population requires a series of pathophysiological and clinical considerations that are essential for a therapeutic approach mainly aimed at the quality of residual life in this subset of patients.

Increase Neuronal Inhibition

In experiments in vitro, three herbs show an affinity for gamma aminobutyric acid (GABA) receptors Matricaria recutita (chamomile), Passiflora incarnata (passionflower), and valerian. GABA receptors are the same receptors that certain medications target. GABA inhibits the firing of nerve cells. This may be why phenobarbital, clonazepam, and valproic acid help control seizures. The patient may feel a stronger sedative effect if these herbs are taken at the same time as the medications. As a result, the patient may require a lower dosage of drug. The scientific literature has not reported any herb-drug interactions between these three botanicals and the aforementioned antiepileptic drugs. By law, N.D.s cannot change prescription medications, but if patients want to reduce their dosage, N.D.s will work closely with all other medical specialists to do so.

Combinations of statins with highdensity lipoprotein cholesterolelevating agents

Similar beneficial effects were expected with statins in combination with fibrates. However, a heightened awareness of the potential for severe side effects with this combination therapy has occurred as more cases of severe myopathy and rhabdomyolysis were observed in clinical trials administering cerivastatin in combination with gemfibrozil than with cerivastatin alone. These results have been attributed to drug-drug interactions occurring as a result of the potent inhibition of CYP2C8, a key metabolizing enzyme of cerivastatin, by gemfibrozil, resulting in elevated plasma concentrations of cerivastatin. These adverse effects contributed to the withdrawal of cerivastatin from the marketplace.

Physiologically Based Models for the Fraction Absorbed

PBPK simulation modeling (see 5.37 Physiologically-Based Models to Predict Human Pharmacokinetic Parameters 5.35 Modeling and Simulation of Pharmacokinetic Aspects of Cytochrome P450-Based Metabolic Drug-Drug Interactions) has developed considerably in recent years.73'74'77'78 In combination with ACAT models it is therefore now possible to simulate the whole body pharmacokinetic events and to predict the human or other species most important pharmacokinetic properties, including estimates of oral absorption. The model parameters are separated into physiological parameters for the species studied and compound-specific parameters, which can be measured or estimated computationally.

Laboratory Graphing and Reports

A wide variety of reports are available in the online patient chart. These include reports for procedures, medication profiles, order summaries, nutritional assessments, pathology reports, and health summaries. A health summary is a special report that makes available a wide variety of clinical reporting components. These components may be configured to create custom reports that provide relevant information for a particular situation.

Modeling of Phase 1 Metabolism Cytochromes P450

Seven of the 57 known human isoforms of cytochromes P450 (CYP1A2, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) are responsible for more than 90 of the metabolism of all drugs in current clinical use.8 Some of these enzymes (especially CYP2D6 and CYP2C9) show polymorphisms, which can either result in rapid or very poor metabolism.9-11 For example, debrisoquine is extensively metabolized in normal individuals to 4-hydroxydebrisoquine, but poor metabolizers can develop high levels of the parent compound, which may be toxic.12 The impaired metabolic oxidation of at least 30 drugs with diverse structures and pharmacological actions has been associated with the phenotype of poor debrisoquine metabolism. In a few cases, poor metabolizers may be unable to bioactivate a parent drug, such as encaimide, to its therapeutically active metabolites.13,14 Binding of any drug to these cytochromes P450 can cause drug-drug interactions, which can lead to severe side effects. This has in the...

Medication Induced Delirium

Principles to remember in cases of drug-induced delirium include the facts that (1) blood levels of possibly offending agents are helpful and should be obtained, but many persons can become delirious at therapeutic levels of the drug, (2) drug-induced delirium may be the result of drug interactions and polypharmacy and not the result of a single agent, (3) over-the-counter medications and preparations (e.g., agents containing caffeine or phenylpropanolamine) should also be considered, and (4) delirium can be caused by the combination of drugs of abuse and prescribed medications (e.g., cocaine and dopaminergic antidepressants).

Basic Science Of Addiction

The terms ''pseudotolerance'' and pseudoaddiction are very important in pain management. Pseudotolerance, as defined by Pappagallo, is the need to increase medication such as opioids for pain, when other factor(s) are present but unappreciated as disease progression, new disease, increased physical activity, lack of compliance, change in medication, drug interaction, addiction, and or deviant behavior (18).

Dsmivtr Diagnostic Criteria

One-third to one-half of the usual initial dose) are advised and only agents with minimal anticholinergic activity should be employed. Appropriate choices would be the selective serotonin reuptake inhibitors such as paroxetine, fluoxetine, sertraline, citalopram, and escitalopram. Although sertraline, citalopram and escitalopram are least likely to cause drug-drug interactions, even these agents have the potential to increase confusion in Alzheimer's individuals. Agents such as trazodone and mirtazapine have occasionally been employed because of their sedating properties. If tricyclic antidepressants are used, the secondary amines (e.g., desipramine, nortriptyline) are recommended over the tertiary ones (e.g., amitriptyline, doxepin). Careful attention to the possible side effects of these agents, particularly orthostatic hypotension, lowering of the seizure threshold, excessive fatigue, urinary retention, constipation, confusion, and accelerated memory impairment, is suggested. Most...

Three Dimensional Approaches to Predicting Toxicity

3D approaches use knowledge about the shape and volume of either the submitted compound or the binding site thought to be involved in the mechanism of toxicity, or both. They often require knowledge that the chemicals act via a common mechanism or biological event. One example where 3D methods have been applied to predict toxicity is the binding or blockage of the potassium ion channel in the prediction of prolonged QT syndrome, another is the identification of substrates for one or more of the P450 cytochromes and their ability to cause induction or peroxisome proliferation. P450 induction where a patient is taking multiple therapeutic medicines has been linked to causing adverse events through prolonged or increased exposure to one of the drugs or decreased efficacy by increased metabolic clearance. This type of effect is often referred to as a drug-drug interaction (DDI).

Role of Human Etheragogo Related Gene in QT Prolongation

Perhaps owing to the unique shape of the ligand-binding site and its hydrophobic character, the hERG channel has been shown to interact with pharmaceuticals of widely varying structure, often at concentrations similar to the levels of on-target activity of the respective compounds. While risk tolerance for QT prolongation may vary significantly depending on indication, development stage, etc., the documented hERG-blocking activity reduces the intrinsic value of the molecule, as it increases risk of clinical failure. Among the indications least tolerant of hERG blockade by the candidate compound are antivirals and antibacterials where high plasma concentrations of the drug are necessary to suppress resistance, and pain management drugs and antipsychotics where overdosing is likely. In addition, drug-drug interactions (e.g., via inhibition of P450 metabolism) may lead to unexpectedly high plasma levels of a drug, which are sufficient to prolong the QT interval. As a general rule, a...

Tyrosine Kinase Inhibitors

Oral imatinib is well absorbed, with a bioavailability of nearly 100 .12 Peak plasma concentration occurs within 4 h of administration, regardless of whether or not the dose is taken with food.13 Following oral administration, the elimination half-lives of imatinib and its major active metabolite are approximately 18 and 40 h, respectively.13 Repeat dosing does not have a significant impact on the drug's pharmacokinetics and accumulation is 1.5 to 2.5fold with daily administration.1213 In-vitro models have established that at clinically relevant concentrations, imatinib is approximately 95 protein bound, primarily to albumin and a1-acid glycoprotein.12 Hepatic enzymes, predominantly the cytochrome P450-3A4 isoenzyme, are responsible for the drug's metabolism.13 Other cytochrome enzymes, such as CYP1A2, CYP2D6, CYP 2C9, and CYP 2C19, also contribute to imatinib's degradation.13 Because many other medications can affect this metabolic system, imatinib is susceptible to alterations in...

Pulmonary Arterial Hypertension

More recently, endothelin antagonists have been evaluated in the therapy of pulmonary arterial hypertension. There are at least two types of endothelin receptors ETA and ETB. Activation of either receptor aggravates pulmonary arterial hypertension, but activation of ETA receptors appears to be more detrimental. A nonselective endothelin antagonist, bosentan (Figure 5), is used in the therapy of pulmonary arterial hypertension. Its use is based on the evidence that endothelin is overexpressed in patients with pulmonary hypertension and that overproduction of endothelin may lead to pulmonary vascular remodeling. Bosentan is active orally and has been shown to produce short-term benefits in patients with pulmonary arterial hypertension it improves exercise capacity and reduces pulmonary arterial pressure.47 Its side effects include liver toxicity (elevation of hepatic aminotransferase in 7-14 of patients), teratogenicity, and drug interactions, since bosentan is a substrate for and...

Drugs Targeting Protease

Number of structures solved using NMR (Yamazaki et al., 1996) provided crucial information for the design of new classes of inhibitors, which, ultimately, became an important new category of AIDS drugs (Vacca and Condra, 1997 Wlodawer and Vondrasek, 1998). All publicly available structures of HIV PR and the related simian retrovirus SIV have been made available on the Web in the HIVdb database (Vondrasek and Wlodawer, 1997 Wlodawer and Vondrasek, 1999). The current version of HIVdb, released in early 2000, contains 142 different structures of HIV-1 PR, of which 35 (25 ) are mutants, and 24 structures of HIV-2 PR of which 14 (58 ) are mutants. The database contains structures of HIV-1 PR in complex with all approved protease drugs, and many other potential drugs and drugs in development about 35 are unofficial releases of structures not available in the Protein Data Bank. This is a useful resource for studying the structural effects of mutations and their influence on drug interactions.

Symptoms And Management

Several factors play a role in opioid choices efficacy, versatility, drug interaction, therapeutic index, availability, cost, and organ function. Opioid agonist antagonists, nalbuphine, butorphanol, and meperidine should not be used.921 The most common potent opioids in the first-line treatment of cancer pain are morphine and methadone, fentanyl, hydro-morphone, and oxycodone if limiting side effects occur with morphine. 24-28 Low doses of a potent opioid can be substituted for weak opioids (by World Health Organization classification). Choices will depend upon the patient's previous opioid experience, comorbidities (renal and hepatic function), and comedications. The type of pain does not play a particularly strong role in the choice of opioids.

Success of Predictions

His current role is to understand the enzymology of biotransformations in human in vitro systems and to assess their relevance in the clinic. He is particularly interested in the prediction of metabolism and potential drug interactions using in vitro and in silico approaches. Her recent publications centred on the incorporation of homo heterotropic cooperativity phenomena associated with CYP3A4 (and other enzymes) into the in vitro-in vivo prediction of either clearance or drug-drug interactions. Her current research activities focus on the mechanism-based prediction of human pharmacokinetics, in particular the contribution of the intestinal CYP and UqTenzymes to the clearance and drug interactions and investigations of time-dependent inhibition interactions. Nick Proctor received his PhD from the University of Manchester, UK, under the supervision of Prof Brian Houston, investigating the impact of drug binding in the predictions of human pharmacokinetics and metabolic drug...

The Regulation of Herbal Medicine

There is a tendency to put great trust in herbs because they are natural and, therefore better than artificially produced pharmaceutical drugs. Herbs are not considered drugs by the FDA, but rather dietary supplements that are largely unregulated, unlike drugs. As a result, the amount of active ingredient can vary between products manufactured by different companies, and even between batches produced by the same company. A company that produces herbs has to provide a reasonable assurance that their products are not harmful and the company cannot claim that its product cures or prevents a disease. Otherwise, a company can make any other claim about the supposed benefits without supporting evidence. No legal requirement stipulates that herb manufacturers list the contents, side effects, safety, efficacy, or drug interaction information on the label. The FDA can only recall an herb if harmful effects are found. This information highlights the fact that patients should find out as much as...

Roles of Transporters in Pharmacokinetics

This huge network of hepatobiliary transporters can give rise to variations in drug disposition between individuals by modulating the uptake or the exit of drugs and their metabolites from hepatocytes. A change in hepatic uptake may have clinical consequences. It may modulate the pharmacological activity of drugs that act via the intrahepatocellular transduction pathways, it may cause hepatotoxicity, or give rise to drug-drug interactions. The concentration of the cholesterol-lowering HMGCoA inhibitors in hepatocytes must be adequate for their pharmacological activity, and most of the statins (e.g., pravastatin, simvastatin, lovastatin, cerivastatin, and pitavastatin) enter hepatocytes via OATP1B1, and to a lesser degree via OAT1B3.131 Recently identified genetic polymorphisms like the SLCO1B3 haplotype *17 are associated with reduced statin clearance by the liver and lower concentrations in hepatocytes they thus have less effect on cholesterol synthesis.132 Large-scale clinical...

Safe and Unsafe Medications for Patients with Kidney Failure

Adverse drug reactions and drug interactions are common in renal failure. Since most drugs and drug breakdown products are excreted via the kidneys, even partial loss of kidney function alters the response to a given dose. Kidney disease may change not only drug elimination, but also drug absorption and distribution throughout the body. One such effect often observed is diminished protein binding of drugs in the plasma, owing to low serum albumin level, thereby increasing the concentration of free drugs in the blood. The amount of free drug in the blood is responsible for the drug's effects. If you take a given dose of drug, the extent to which the drug gets bound to your serum albumin will have a major effect on your response The less drug that gets bound to albumin, the greater the drug's effect on your body. Thus a lower dose of the drug may be better for you.

Development of Gabapentin for Epilepsy

After the gabapentin product launch, gabapentin was used extensively by physicians for treating epilepsy. Because of a relatively benign adverse event profile and few drug-drug interactions, it was also prescribed for off-label indications, including neuropathic pain, anxiety, and other psychiatric indications, essential tremor, spasticity, postsurgical pain, and prevention of postmenopausal hot flashes. None of these additional indications were supported in the gabapentin product labeling or approved by regulatory agencies until the FDA approved a supplemental NDA for gabapentin to treat postherpetic neuralgia in July 2001 (see Section 8.18.3.3, below).

Herbal Therapy in Epilepsy

The use of complementary and alternative medications (CAM) in the United States has skyrocketed in the past decade. A 1998 study in the Journal of the American Medical Association estimated that the use of herbal medications increased from 2.5 to 12.1 in the adult population between 1990 and 1997, and that 18 of all prescription drug users were also taking herbal remedies or high-dose vitamins (1). The clinical benefit of CAM is largely unproven, because of a paucity of rigorous clinical trials evaluating safety and efficacy. Patients tend to underreport their use of alternative medicines to physicians, and physicians may discount their significance even when their use is presented. Substantial risks, however, are associated with the use of these interventions. These risks involve the direct toxicities of the alternative preparations as related to their intended ingredients, possible adulteration by other compounds, and interactions that we call herb-drug interactions. Herb-drug...

An Intriguing Opportunity to Go Back to the Future by Revisiting Ones Roots

Figure 16 Drug-drug interaction plot for two drugs A and B.303 EC50, T is the total concentration of the combined drugs which gives 50 of the maximum possible effect. The EC50, T is shown as a function of the fraction of drug A (drug B's fraction is one minus the fraction shown). Rescaling of drug concentrations to units of their EC50 allows simple additivity to be set at unity such that deviations below or above this line indicate synergism or antagonism, respectively. The dots are actual experimental results obtained for two anticancer agents, wherein the observed EC50, T values reflect 20 rays of fixed drug fractions as estimated from the data along that ray alone. The fitted curve was generated by a global model for the entire data set and indicates the complicated nature of interaction relationships within even a well-controlled cell culture environment. That synergism can be accompanied not only by simple additivity but also by ratio-dependent antagonistic relationships is...

Major Depressive Disorder

Elimination half-life of approximately 6 weeks when considered with its potent metabolite norfluoxetine. Sertraline, citalopram, and escitalopram have few potential drug-drug interactions, but all can have gastrointestinal side effects including nausea, vomiting, and diarrhea, as well as sleep alterations, weight changes, sexual dysfunction, and extrapyramidal effects such as a high-frequency, low-amplitude tremor. The tricyclics produce significant anticholinergic effects and may induce delirium, cognitive slowing, urinary retention, dry mouth, and orthostasis these are not recommended for routine use in this vulnerable population. Similarly, monoamine oxidase inhibitors are not recommended for patients with HIV and AIDS. This class of medications poses an extraordinary risk, since persons with HIV and AIDS are often on complex and frequently changing drug regimens and also have the concurrent risk of hypertensive crisis if exposed to certain foods or other medications. These include...

Sleep Disturbance In

Anxiolytics and or antidepressants are usually effective in decreasing anxiety, although the use of anxiolytics in patients with a history of substance abuse may raise another set of issues. The possibility of drug-drug interactions with highly active antiretroviral therapy (HAART) may also limit the choice of agent.

Use of specific antibodies

The problem of some of the specific inhibitors lies in their poor specificity and potency although they are preferred to antibodies in drug-interaction studies. However, the use of inhibiting antibodies has been recently promoted62,63 in the quantitative assessment of a particular CYP in the metabolic pathway of a drug, in particular when several CYPs are involved.64 Much improvement has been made in their selectivity, with reduced cross reactivity between homologous CYPs (e.g., 1A2 and 1A1).

Pharmaceutical Industry and FDA Perspective

According to the FDA, severe hepatotoxicity is one of the most common causes for pharmaceutical product recalls and labeling changes, and this raises the question of how effective nonclinical and clinical testing are in recognizing such toxicity. Although much attention has been focused on the predictivity of animal models for clinical findings in humans, clinical trials of pharmaceuticals are in fact a relatively poor source of information for ascertaining the probability that an event observed in an animal model is also observed in the human. Of critical importance to avoiding unanticipated toxicity in human is the need to understand why drugs that were judged safe to administer to humans on the basis of animal data sometimes cause unexpected toxicity or drug interactions. In other words, why do animal models in these cases fail to predict human hepatotoxicity It is probably even more important to understand why these models sometimes fail to identify hepatotoxic potential in humans...

Descriptive Epidemiology of Herbal and Vitamin Poisonings

An herb is a leafy plant without a woody stem, but herbal preparations include all natural, alternative, and traditional remedies. Twenty-five percent of current, proprietary pharmaceuticals come from plant-herb sources. As a result of the Dietary Supplement and Health Education Act of 1994, the FDA has no authority over regulating herbal and vitamin products, unless they prove to be toxic. 80 of the world's population use herbal products and vitamins daily most are benign, and offer no health benefit (e.g., vitamin C and Echinacea) or potentially lethal drug interactions (e.g., St. John's wort and SSRIs garlic, ginkgo, and ginseng, and anticoagulants ASA, heparin, warfarin ). The most popular herb sales in the United States include Echinacea (10 ), garlic (10 ), goldenseal* (7 ), ginseng (6 ), Ginkgo (4.5 ), and saw palmetto (4.4 ). * Goldenseal is often used illicitly in unsuccessful attempts to disguise urinary marijuana (THC) metabolites. There are no toxicologic databases on...

Safety concerns with statins

Cerivastatin 7, an extremely potent third-generation statin, was withdrawn from patients postapproval in 2001 after a higher incidence of severe myopathy and renal failure was observed in cerivastatin-treated patients even though they were taking doses up to 100 times lower than those treated with other statins to achieve their LDLc-lowering target. The mechanistic basis for this increased risk with cerivastatin alone has not been determined. However, more cases of severe myopathy and rhabdomyolysis were observed in clinical trials using cerivastatin in combination with gemfibrozil 13 than with cerivastatin alone. These results have been attributed to drug-drug interactions that occurred as a result of potent inhibition of cytochrome P450-2C8 (CYP2C8) by gemfibrozil 13, one of the key metabolizing enzymes of cerivastatin, resulting in elevated plasma concentrations of cerivastatin.

Nfectious Disease

Harn, Jr., pud, 2006 Drug Interactions in Infectious Diseases Second Edition, edited by Stephen C. Directions in Drug Discovery, edited by Philip J. Rosenthal, md, 2001 Drug Interactions in Infectious Diseases, edited by Stephen C. Piscitelli, pharmd

Excretion

The total elimination of a parent compound and metabolites requires the integrity of these three separate processes, which themselves depend on plasma pH, urine pH, and renal blood flow. All active processes may be restricted by the amount of available transporters and energy supply, which may lead to competitive drug-drug interactions.

Diagnosis

Chronic overdose Chronic renal failure (CRF) in the elderly and alcoholics bleeding and cognitive dysfunction and dementia in elderly. Constellation of side effects Gastrointestinal, renal, hypersensitivity reactions, (acetic acids and phenylbutazone piroxicam propionic acid) pulmonary, CNS, hematologic, drug-drug interactions.

Toxicity

Mechanism Increased norepinephrine and epi-nephrine effects tachycardia and hypertension, headache, angina, myocardial infarction (MI), cerebrovascular accident (CVA), cardiovascular collapse. Increased 5-HT and Dopa-mine effects agitation, delirium, obtundation, nystagmus, hyperreflexia, tremors, myoclonus, muscle rigidity, hyperthermia, diaphoresis, seizures, respiratory depression. Interactions (1) Drug interactions all sympathomimetic drugs, SSRIs, cocaine some opioids (codeine, meperidine, and dextromethorphan) (2) foods high in tyramine aged cheeses, red wines, pickled or smoked meats and fish.

Pept12

An examination of a database containing data assembled from the literature on substrates inhibitors for various transporters indicates how the research community has scored their relevance for drug transport (Figure 5).99 Clearly, the extensively studied efflux protein P-glycoprotein (P-gp) has the highest number of substrates inhibitors, followed by other efflux transporters of the ATP-binding cassette (ABC) transporter family, various transporters for organic anions, cations, and the oligopeptide transporter PEPT1.99 This rating can probably be explained by the role of ABC transporters in drug resistance,100'101 brain uptake,102'103 and drug-drug interactions,104-106 and by the importance of ABC transporters and organic anion and cation transporters for drug transport and elimination in the liver, kidney, and, perhaps, the intestine,107 and by the exploitation of PEPT1 as a (pro)drug target for enhanced absorption.108 Examples of successful exploitation of PEPT1, which is...

Arry142886 Azd6244

The inhibitor has excellent pharmacokinetics in both mice and rats, with high bioavailabilities (82 and 74 , respectively) 113 . Additionally, the potential for drug-drug interactions after administration of ARRY-142886 is low as it does not inhibit any of the major cytochrome p450 isoforms below 20 M.

Drug History Taking

If the patient is on an antiretrovi-ral, the patient may stop taking the medication because he or she is feeling uncomfortable symptoms of opioid withdrawal. Other drug-drug interactions, including those with psychotropic medication, are also significant. A patient with comorbid HIV and hepatitis C who stops all alcohol use during interferon treatment and eagerly resumes daily use after successful treatment and eradication of hepatitis C virus puts his or her hepatic function in jeopardy once again. For individuals who have unprotected sexual encounters in the context of alcohol or drug use, history-taking has public health implications. For individuals exposed to drug- or alcohol-related domestic violence, the implications are both tragic and obvious. Hence, for medical, psychological, and social reasons, a comprehensive drug history is essential in persons with HIV and AIDS.

Asp266

More recently the crystal structure of the LBD of human PXR was elucidated and showed the existence of an extensive hydrophobic ligand-binding cavity containing several polar residues, which allow hPXR to bind to a variety of structurally diverse ligands including small and large molecular weight compounds 54 . Furthermore mutagenesis analyses indicated that alteration of four amino acids in the ligand-binding pocket of mPXR to the corresponding hPXR amino acids (Arg203 Leu, Pro205 Ser, Gln404 His, and Gln407 Arg) was sufficient to switch the original PCN responsive mPXR to a human-like receptor, which could be activated effectively by SR12813 but no longer by PCN (Figure 4.66). Using trans-species transfection assays, Xie et al. 11 demonstrated that co-transfection of hPXR into primary rat hepatocytes resulted in a significant induction of rat CYP3A23 reporter gene by compounds known to be human PXR activators and CYP3A4 inducers, including rifampi-cin, clotrimazole,...

NCE product launch

Figure 2 Classical drug discovery and development paradigm.28,31-36 This model portrays interactions with US regulatory agencies and uses terms related to those interactions for steps 11 to 17. All of the other terms typify generic phrases that have been commonly used by the international pharmaceutical community. While some of the noted activities can be conducted in parallel or in an overlapping manner, the stepwise, sequential nature of this paradigm's overall process is striking. Furthermore, whenever a progressing compound fails to meet criteria set at an advanced step, the process returns or draws again from step 3 for another reiteration. Numerous reiterations eventually identify a compound that is able to traverse the entire process. A successful passage through the entire process to produce just one product compound has been estimated to require about 15 years at a total cost of about 500 million. While the largest share of these time and cost requirements occur during the...

Treatment

Treatment of anxiety disorders in HIV-positive patients follows guidelines similar to those for treating persons with other chronic medical illnesses, with particular attention to medication dosing, metabolism, potential for drug interactions, and potential for side effects (Farber and McDaniel, 2002). This will be discussed further in Chapter 32. While the DSM-IV guidelines prove helpful in diagnosing specific disorders, it is generally more appropriate to treat the anxiety on the basis of a patient's symptoms and symptom severity. To minimize adverse effects, medications should be started at low doses and titrated up slowly to the desired effect. Side effect profiles should also be taken into account. Selective serotonin reuptake inhibitors (SSRIs) are useful as first-line therapy for treating chronic anxiety disorders (Ferrando and Wapenyi, 2002, Pollack et al., 2004), although benzodiazepines are most frequently used (Cabaj, 1996). Benzodiazepines are especially useful as an...

Metabolism

CYPs may be induced by a structurally diverse range of xenobiotics including rifampicin, omeprazole, and phenobarbital, as well as cigarette smoking and alcohol.49 The induction of CYPs leads to two different problems effects on self, and coadministered drug-drug interactions. On chronic administration ritonavir induces CYP3A leading to a decrease of its own AUC.50 Regarding the latter effect, an inducible drug can influence the pharmacokinetics of a coadministered drug which shares the same metabolic pathway. For example, rifampicin induces metabolism of ethynylestradiol which can lead to the failure of contraceptive therapy.49 More sophisticated approaches accounting for drug interactions with transporter proteins51,52 and metabolizing enzymes are required to enable accurate predictive models to be developed.

In Silico Approaches

The application of in silico approaches for the modeling of drug-protein interactions has several stages, depending on the level of knowledge available on the structure and function of the modeled protein. Lack of detailed information about the 3D structure of the multidrug transporters and the binding sites involved in the drug interactions precludes the use of in silico tools that are based on the so-called structure-based drug design approach (e.g., docking and, related to it, virtual screening). Instead, they are commonly restricted to ligand-based drug design methods. Among the mostly used are different versions of the classical quantitative structure-activity relationship (QSAR) analyses by Hansch118 and Free-Wilson119 three-dimensional quantitative structure-activity relationship (3D-QSAR), comparative molecular field analysis (CoMFA),120 and comparative molecular similarity indices analysis (CoMSIA).121 Furthermore, correlations with molecular descriptors can be generated from...

Clinical features

An MSLT performed alone has the same drawbacks as does pupillography -it measures sleepiness regardless of its cause, which may simply be sleep deprivation. The MSLT also ignores repetitive microsleeps that can lead, in borderline cases, to daytime impairment not scored by conventional analysis. To be clinically relevant, the test must be conducted under specific conditions. Subjects must have abstained from medication for a sufficient period (usually 15 days) so that drug interaction is avoided. On the basis of sleep diaries, their sleep-wake schedules are stabilized. On the night preceding the MSLT, the subjects undergo a standard nocturnal polysomnogram. Throughout the total nocturnal sleep period, any sleep-related biological abnormalities responsible for sleep fragmentation and sleep deprivation are recorded. A nocturnal polysomnogram is useful for eliminating other possible causes of excessive daytime sleepiness such as periodic leg movements and obstructive sleep apnea. The...

Retinoids

Tretinoin, as an oral preparation, is well absorbed into systemic circulation, with a peak plasma concentration between 1 and 2 hours after oral administration.42 Food increases the bioavailability of tretinoin however, the clinical significance of this is unknown. The activity of intravenous liposomal tretinoin has been evaluated, but demonstrated no clear advantage when compared with standard oral tretinoin.43 The drug undergoes hepatic metabolism via the cytochrome P450 system. The degradation of the parent compound results in the formation of four identified metabolites 13-ris retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide.42 Tretinoin acts as both an inhibitor and a substrate of the cytochrome P450 enzyme and therefore the product is susceptible to potential drug interactions. Tretinoin is greater than 95 protein-bound, predominantly to albumin. The

Cooh

The substrate specificities of transporters are often very broad, as indicated by the many overlaps of substrates and inhibitors, much like the specificity of the drug metabolism enzymes. Thus, probenecid was initially known to produce many drug interactions by blocking the secretion by the kidney of many drugs, including the penicillins and the antiviral Tamiflu.116 Probenicid is today known to be a polyspecific inhibitor of several MRPs, OATs, OATPs, and even OCTs.117 Similarly, MRP1, MRP2, and MRP3 have broad, overlapping substrate specificities, while OCT1, OCT2, and OCT3 transport a wide range of similar OCs. P-gp interacts with a multitude of xenobiotics, many of which are metabolized by CYP3A4 5, and some of them are also substrates of MRP1 and BCRP.21 The tyrosine kinase inhibitor imatinib is effluxed by both P-gp and BCRP, and imported by OCT1.118 Thus all ionized chemicals, peptides, and nucleosides that cannot diffuse freely across membranes are very likely to interact with...

Ginseng

Side effects and drug interactions are possible with the use of Asian ginseng and Siberian ginseng. Both herbs may produce sedation and may conceivably worsen MS fatigue or accentuate the sedating effects of medications and alcohol. Asian ginseng may interact with steroids, which sometimes are used to treat MS attacks. Asian ginseng and Siberian ginseng may increase bleeding tendency and should be avoided by people who are undergoing surgery, people who have blood-clotting disorders, and people who take blood-thinning medications or aspirin.

Amphotericin B

Imidazoles Miconazole, clotrimazole. Toxicity Increased drug-drug interactions Drug-drug interactions Azoles inhibit CYP3A4, responsible for metabolizing many drugs, including statins, H1-blockers, steroids, benzodiazepines, calcium channel blockers (CCBs).

Antivirals

Due to viral resistance and emergence of HIV-1 mutants, attempts have been made to design novel antiretroviral drugs (Imamichi, 2004) to suppress the replication of the resistant variants. Among the first drugs to satisfy this need was enfuvirtide. Enfuvirtide belongs to the third family of antiviral (Barbaro et al., 2005), and is an HIV fusion inhibitor (FI). This drug has a unique mechanism of action involving HIV entry at the stage of membrane fusion. Its antiviral activity and favorable safety and tolerability features have been demonstrated in combination with other agents. It is claimed that the drug offers a low potential for cross-resistance with other anti-retroviral drugs and its extracellular distribution means that drug interactions and intracellular metabolic disturbances are unlikely (Lazzarin, 2005).

Pravastatin

The successful introduction of HMG-CoA reductase inhibitors for lipid lowering sparked intense competition in the field. pravastatin 4 (Figure 7) is made in a two-step fermentation process that first generates compactin with Penicillium citrinum, and after hydrolysis of the lactone, employs a biological hydroxylation with Streptomyces carbophilus to introduce the allylic 6-alcohol group regioselectively. Pravastatin has higher water solubility and provided several potential advantages over the more hydrophobic analogs, lovastatin and simvastatin. Unlike lovastatin and simvastatin, pravastatin sodium is administered as the sodium salt of the corresponding open-chain hydroxy-acid. The polar nature of pravastatin, however, limited its overall human absolute bioavailability to 17 , presumably due to incomplete absorption and firstpass metabolism. However, pravastatin has been used to demonstrate the facilitated cellular uptake of compounds through organic anion transporter proteins....

Absorption

A cornerstone of the treatment of CKD patients is the use of phosphate-binding agents. Aluminum is rarely used any more, but calcium, magnesium, and lanthanum-based agents all pose the possibility of chelation of drugs as well as the intended gastrointestinal phosphorus. Tetracycline chelation to antacids is well known to clinicians, but tetracycline is not used often in the CKD patient population. Of more importance to caregivers of CKD patients is the well-described drug interaction of fluoroquinolones (e.g. ciprofloxacin, levofloxacin, ofloxacin, etc.) and metal-based phosphate-binding antacids. In a study by our research group, oral cipro-floxacin bioavailability was reduced by 51 when given simultaneously with four 667-mg calcium acetate tablets 9 . It is not only that there is a reduction in the percent of the fluoroquinolone absorbed that is a problem. The pharmacodynamics of fluoroquinolones suggest that they are more effective when high peak serum concentrations are achieved....

Conclusion

The recent expansion of our knowledge of the involvement of drug transporters in pharmacokinetics has added a new layer of complexity to our understanding of the mechanisms underlying the absorption, distribution, and elimination of drugs. New transporters undoubtedly remain to be identified, and the functions of some identified transporters remain poorly understood. Nevertheless, it is clear that the drug transporters in organs such as the intestine, liver, brain, and kidney are significant determinants of variations in drug responsiveness between individuals. Together with the drug-metabolizing enzymes, they determine drug-drug interactions, drug-induced organ toxicities, and diseases. Detailed knowledge of genetic polymorphisms in transporters and how they affect transporter function will help to optimize drug therapies and identify unknown, residual factors that influence intersubject variations.

Treatment Strategies

Underlying depression should be treated with selective serotonin reuptake inhibitors (SSRIs), which are generally better tolerated than tricyclic antidepressants by patients with HIV and AIDS (Elliot et al., 1998 Schwarz and McDaniel, 1999). The notable exception is fluvoxamine, which is less well tolerated despite its efficacy in treating depression (Grassi, 1995). Since fatigued patients with HIV and AIDS are especially sensitive to antidepressant side effects compared to patients without fatigue (Sharpe and Wilks, 2002), treatment should be initiated at very low doses. Because concomitant antiretroviral therapy is frequently used, drug-drug interactions should also be carefully monitored by prescribing physicians. Excellent reviews of such psychopharmacologic considerations have been carried out by Robinson and Qagish (2002) and