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Drug Interactions With Cannabinoids

The potential for more spectacular drug interactions to occur seems greatest when cannabinoids are consumed for pleasure, often in high doses and frequently as a cocktail with other psychoactive substances, over the counter medicines and alcohol. One would anticipate a much lower threat during the more controlled, measured use of these agents to treat a disease under medical supervision.

Clinical Importance Of Drug Interactions

36 The term drug-drug interaction is also used, to make the distinction from drug-food interactions, and interaction with endogenous transmitters and hormones. one time, the number of possible combinations would be more than 64 million. There can be no doubt that the number of drug interactions that might occur in this imagined situation would be too large to commit to memory or to paper. But the observation that one drug can be shown measurably to alter the disposition or effect of another drug does not mean that the interaction is necessarily of clinical importance. In this section we highlight the circumstances in which clinically important interactions can occur we describe their pharmacological basis and provide a schematic framework to identify potential drug interactions during clinical practice. Clinically important adverse drug interactions become likely with the following

Drug interactions

When a drug is administered, a response occurs if a second drug is given and the response to the first drug is altered, a drug interaction is said to have occurred.36 A drug interaction may be desired or undesired, i.e. beneficial or harmful. It is deliberately sought in multidrug treatment of tuberculosis and when naloxone is given to treat morphine overdose. It is an embarrassment when a woman taking a combined oestrogen progestogen oral contraceptive for a desired interaction is prescribed a drug that is a metabolic enzyme inducer, with the result that she becomes pregnant. Although dramatic unintended interactions attract most attention and are the principal subject of this section they should not distract attention from the many therapeutically useful interactions that are the basis of rational polypharmacy. These useful interactions are referred to throughout the book whenever it is relevant to do so.

Cellular Toxicology Assays

Developing useful assays for screening drug effects against the HERG channel has become extremely important to the pharmaceutical industry. Drug screening in humans or animals is most physiologically relevant. However, this method is not always ethical, it is very low throughput, and it is difficult to identify the molecular target of any drug interactions. The patch-clamp method has proven very powerful in its sensitivity and ability to evaluate channels at the single molecule level. However, patch-clamp technology is expensive, difficult, low throughput, and far removed from a physiologically relevant context. Cell culture-based assays have been developed that use fluorescent dyes sensitive to plasma membrane potential in conjunction with plate readers and flow cytometry. These assays have proven to be high throughput but often suffer from decreased sensitivity or difficulty in maintaining cell lines. The need exists for a sensitive, high-throughput, cost effective, and...

Individual risk factors

While cyclosporine is an intrinsically nephrotoxic drug due to a direct action on the kidney, under other circumstances it can become nephrotoxic in the presence of a second drug, exhibiting a so-called drug-drug interaction. For example, drugs that inhibit the hepatic P-450 drug-metabolizing enzymes can cause a significant change in cyclosporine pharmacokinetics and, thus, render an otherwise stable dose nephrotoxic 126 . Drugs that induce such changes in cyclosporine levels include erythromycin, fluconazole, ketoconazole, ci-metidine. Another example of drug-drug interaction occurs when non-steroidal anti-inflammatory drugs are given to patients receiving anti-hypertensive drugs 127 . Due to the action of the NSAID to inhibit prostaglandin synthesis, the loss of endogenous induced vasodilatation causes the blood pressure to become uncontrolled often necessitating increasing the current anti-hypertensive drug dosage or prescribing additional anti-hypertensive drugs 128 . Recently,...

7 High Content Metabolic Assays

Efforts for the rapid screening of drug adsorp- tion metabolism have intensified as the imports tance and relevance of the parameters for drug discovery have become more apparent with every failed and recalled drug. The cyto- chrome P450 (CYP) enzymes metabolize xe-I nobiotics and evolved as a defense against ac-I cidentally ingested toxic compounds. Drug pharmacokinetics are modulated in part by metabolism and patients on multi-drug regimens can experience unexpected changes, both positive and negative, in drug mean residence time and maximum serum levels. Drug I inhibition of CYPs can lead to increased drug levels and increased risk of toxic side effects. Several high-throughput assays for test comI pound inhibition of CYPs have been reported I (36-38).Most are based on changes in the flur orescence of a known CYP substrate and speI cificCYP isoform inhibition in the presence of I test compounds. Increased CYP activity can result in toxicity as well. The nuclear hormone I receptor...

Renal tubular secretion of drugs xenobiotics

Secretion is not uniform along the proximal tubule, and may differ between superficial and juxtamedul-lary nephrons. This heterogeneity of secretion, varying between species and substrates, might reflect different densities of carrier molecules along the tubule 19 . Since the number of carrier molecules is limited, secretion is saturable and subject to competition between substrates. Such competition may thus result in drug interactions some of them being of clinical relevance (see below) 43 .

The Use Of Biochips For Elucidating The Mechanism Of Drug Action

To this point, our analysis has focused on the identification of potential drug targets using life cycle expression profiling and elucidation of gene function. A reverse approach could provide additional insight. When micro-organisms or tissues are treated with small molecules that inhibit basic cellular processes, genes in the inhibited pathway may be transcriptionally up- or downregulated (Evans and Guy, 2004 Gunther et al., 2003 Hatzixanthis et al., 2003 Reinoso-Martin et al., 2003 Schuller et al., 2004). This observation leads to the evaluation of the global transcriptional response to drug treatment, a useful tool for identifying the cellular processes affected by the drug, as well as for finding new potential targets within the affected pathway. Today, despite many years of investigation, the mechanisms of action of the most effective antimalarials such as quinoline, antifolate, or artemisinin-derivatived compounds remain uncertain. To identify genes implicated in drug...

Principles Of Personalized Medicine

Varying efficacy and toxicity have implications not only for the patient but also for the health-care system. Currently available anticancer drugs show limited efficacy in as many as 70 of treated patients, and adverse drug reactions caused by the failure to predict individual drug toxicity or toxic drug-drug interactions now accounts for 100,000 patient deaths and two million hospitalizations in the United States every year (3). Serious adverse drug reactions are the sixth leading cause of death in the United States (4), which costs the health-care system billions of dollars (5). Identifying drug-specific predictive markers would help individualize therapy, ensuring cost-effective management that has maximal therapeutic efficacy with minimal toxicity.

Pharmacokinetic and ADME Studies

As part of the drug discovery and development process, pharmacokinetic and ADME studies have become an integral step in the early evaluation of drug candidates. Absorption, half-life, and metabolism are being measured early in the development of a drug candidate in order to exclude those compounds that are poorly absorbed or rapidly metabolized or eliminated. Traditionally, most ADME studies have been carried out in vivo, usually in mice, rats, and dogs. However, increased knowledge of human drug metabolism, as well as the increased availability of human tissues, have led to a greater use of in vitro metabolism studies, using preparations from human tissues, in early drug development. The metabolic profile, as well as species differences in metabolism of the drug candidate can be obtained. Data obtained from these studies can help determine the human enzymes that are responsible for the metabolic clearance of the compound, and the choice of the most appropriate animal species to be...

Clinical Features

As with other forms of proarrhythmia, higher drug doses and concentrations are generally thought to increase risk, and patient-specific characteristics (notably the presence of diseased myocardium) are believed to modulate this risk. Propafenone is metabolized almost exclusively by CYP2D6, but the downstream metabolite, 5-hydroxy-propafenone, is also a sodium channel blocker. Therefore, in individuals with deficient CYP2D6 activity (either on a genetic basis or due to drug interactions), the parent drug accumulates, with somewhat more sodium channel block, as assessed by QRS prolongation. This is generally not clinically significant. The parent molecule does have P-blocking activity, whereas the metabolite does not, and so adverse effects due to P-blockade are more common with the deficient CYP2D6 activity (Lee et al. 1990). Flecainide is also a CYP2D6 substrate but is also excreted unchanged by the kidneys. Therefore, the CYP2D6 genotype generally has little effect on flecainide...

Profile of Proton Pump Inhibition

Comparative studies with lansoprazole and pantoprazole suggest that they have a potency similar to that of omeprazole (143). Rabepra-zole is readily converted to the active drug form and has a more rapid onset of effect than that of omeprazole in both in vitro and in vivo studies. In the rat, there is evidence to suggest that rabeprazole may have a slightly shorter duration of action than that of other PPIs. Compared with lansoprazole, the onset of action of rabeprazole was faster and its duration of action was shorter, as determined by measuring acid output and microsomal enzyme activity (144). However, in another study in dogs, the rate of recovery of acid output was similar when rabeprazole was compared with omeprazole (145). The rate of activation of PPIs is pH dependent, with rabeprazole being fully activated at pH 5.0, whereas omeprazole and lansoprazole are only partially activated. These different pH selectivities may have an impact on drug interactions and safety (146)....

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.

Mutations andor Polymorphisms May Increase Susceptibility to Drug Induced Arrhythmias

Within the context of arrhythmia, pharmacogenomic considerations are important to determine the potential for genetic heterogeneity to directly affect drug targets and interfere with drug interactions. Mutations or polymorphisms may directly interfere with drug binding (Liu et al. 2002) or can result in a physiological substrate that increases predisposition to drug-induced arrhythmia (Splawski et al. 2002).

Clinical Applications

2.2 Side Effects, Adverse Effects, Drug Interactions Contraindications Table 6.4 provides the side effects, adverse effects, and drug interactions and or contraindications for the listed anticonvulsants. Additional explanations as noted in the table are provided as follows. Phenytoin. As with all anticonvulsants, phenytoin included, their central side effects include drowsiness and or dizziness. In addition, phenytoin also produces blurred vision that may be serious to those individuals who operate heavy machinery. The adverse effects with phenytoin can occur to the cardiovascular system when the agent is administered rapidly by the intravenous route. Atrial and ventricular conduction depression and ventricular fibrillation have occurred, particularly with the elderly or seriously ill patients (18). Gingival hyperplasia occurs frequently with this agent and may be reduced with good oral hygiene. Drug interactions with phenytoin are widely distributed and include valproic acid, which...

Molecular and Biophysical Determinants of Isoform Specificity

There are many factors that contribute to efficacy of VGSC blockade. Drugs have variable affinity to different isoforms, and implicit tissue properties such as resting potential, action potential morphology, and action potential frequency affect in vivo drug responses. For example, antiarrhythmic agents are highly cardioselective and bind with higher affinity to cardiac sodium channel isoforms compared to brain and skeletal muscle. There is some debate as to the molecular mechanism of cardioselectivity Does it result from intrinsically higher drug binding affinity (Wang et al. 1996), or as a secondary effect of isoform-specific kinetics (Wright et al. 1997), which may increase the probability of drug interaction with the binding site

Safety and Efficacy Versus Toxicity Ratio

Unique and important drug interactions occur in the pediatric population. For example, infants have special needs for certain dietary components, such as vitamins, amino acids, and calcium, to maintain normal growth and development. The efficacy of these dietary elements may be enhanced or diminished by drugs. Calcium (found in milk), for example, significantly interferes with the absorption of some antibiotics, limiting their therapeutic effectiveness. In addition, antibiotics can alter the intestinal flora, potentially resulting in diminished absorption of certain vitamins. Although the same may be true in adults, one normally does not attach the same importance to these ancillary

Structural Basis of Kr Blockade

Fig. 2a,b Structural model of the drug-binding site in the KCNH2 channel. a The structures of two of the four subunits that form the pore and inner cavity of KCNH2 and Kv channels are shown. The inner helices and loops extending from the pore helices to the selectivity filter form the inner cavity and drug-binding site of HERG. Several structural features that help explain the nonspecific drug-binding properties of HERG are illustrated. The inner cavity of HERG is long, creating a relatively large space for trapping drugs and for channel-drug interactions. Aromatic residues (black) not found in Kv channels are critical sites for interaction for most compounds, but not for fluvoxamine. Other sites for drug interaction are polar residues (gray) located close to the selectivity filter. Kv channels have a Pro-X-Pro motif that is proposed to insert a 'kink' in the inner helices, resulting in a relatively small inner cavity. The inner cavity is lined by aliphatic rather than aromatic...

Na Channel Blockers Diagnosis and Treatment

Na+ channel blockade by flecainide is of particular interest as it had been shown to reduce QT prolongation in carriers of some Na+ channel-linked long QT syndrome type 3 (LQT3) mutations, and to evoke ST-segment elevation, a hallmark of the Brugada syndrome (BrS), in patients with a predisposition to the disease (Brugada et al. 2000). Thus in the case of LQT3, flecainide has potential therapeutic application, whereas for BrS it has proved useful as diagnostic tool. However, in some cases, flecainide has been reported to provoke BrS symptoms (ST-segment elevation) in patients harboring LQT3 mutations (Priori et al. 2000). Furthermore, flecainide preferentially blocks some LQT3 or BrS-linked mutant Na+ channels (Abriel et al. 2000 Grant et al. 2000 Liu et al. 2002 Viswanathan et al. 2001). Investigation of the drug interaction with these and other LQT3- and BrS-linked mutations may indicate the usefulness offlecainide in the detection and management ofthese disorders and determine...

Structural Basis of IKs Block

Investigation into the structural determinants of IKs block has only begun recently. Preliminary studies revealed a common site for binding of IKs blockers, including chromanol 293B and L-735,821 (L7), in the S6-domain (F340) of the KCNQ1 subunit (Fig. 3). Other putative interaction sites in the S6-domain (T312 and A344) and the pore-helix (I337) may lend specificity to pharmacological interactions (Seebohm et al. 2003). Interestingly, these binding sites are located near an aqueous crevice in KCNQ1 that is thought to be important for interactions with KCNE1 that allosterically affects pore geometry (Kurokawa et al. 2001b Tapper and George 2000, 2001). Drug interaction sites for channel agonists stilbene and fenamate have also been elucidated on extracellular domains in KCNE1 (Abitbol et al. 1999 Fig. 3).

Molecular Determinants of Drug Binding

Much evidence suggests that antiarrhythmics bind in the pore of the channel on the intracellular side of the selectivity filter (Ragsdale et al. 1994, 1996). Mutagenesis experiments have revealed multiple sites that affect drug binding on the S6 segments of domains I, III, and IV, and that dramatic changes in drug affinity can result from mutations near to the putative drug receptor sites on DIVS6 (Fig. 8). For example, mutations of I409 and N418 in DIS6 moderately altered drug interaction affinity in the brain VGSC NaV1.2 (Yarov-Yarovoy et al. 2002). Mutagenesis studies of DIIIS6 in NaV1.2 suggest that L1465, N1466, and I1469 are involved in drug binding, since mutation of these residues reduced affinity of the LA etidocaine (Yarov-Yarovoy et al. 2001). Experiments using the rat skeletal muscle isoform found that residues corresponding to human NaV 1.2 L1465 (L1280) and S1276 modulated LA affinity as well as the affinity of the channel activator batrachotoxin (Wang et al. 2000b Nau...

Drug Development Issues

As indicated previously, these expanded-use conditions often foster the recognition of adverse events and drug interactions that would not be recognized during the more restrictive controlled trials. The expanded-use protocol is complex and demanding. It increases the company's demand for monitoring resources because the sites are often scattered across the country, and each might enroll only a few patients, either because the number of eligible patients is limited or because the sites conducting the expanded-use protocols may not be experienced in conducting investigational drug trials and may not enroll larger numbers.

Medications Indications Dosing Adverse Effects

Concerns about cost, compliance, and drug interactions have given polypharmacy a pejorative connotation, but chronic HF is a classic exception to the notion that less is more. Few patients relish a regimen of multiple pill taking, but chronic HF is a typical disorder in which multiple drugs offer clear-cut advantages compared to monotherapy. The challenge, then, is making it work in real life. Educating patients about their condition and motivating their adherence to a course of therapy are steps towards success. A clear and comprehensible explanation of the basic purpose and action of each drug is a time-consuming process, even for expert and trained physicians and staff members. Patients' understanding of drug regimens should be periodically refreshed by delegated staff members (nurse coordinator, clinical nurse specialist, nurse practitioner, physician assistant) responsible for the educational monitoring of patients.

Study Data From The Expanded

It is the rare patient who suffers from an isolated disorder and takes only a single medication. In the expanded-use protocol, much information can be gained by evaluating potential drug interactions with the current medications the patient may be taking. Frequently, this information has tremendous impact on the overall therapeutic efficacy of the investigational drug and its risk and benefits when given with other forms of therapy.

Cardiac Allograft Vasculopathy

CYP3A4 and the risk of relevant drug interaction appears to be lower. Obesity can be controlled by daily exercise and a healthy diet. Cessation of smoking is a prerequisite for transplantation in most centers but psychological support may be needed not to resume old habits. Hypertension is linked to immunosuppressive therapy and dener-vation of cardiac volume receptors. It is very common and affects 73 by 1 year and 97 by 7 years.1 It is sensitive to a low-sodium diet. Treatment with diltiazem and ACE inhibitors led to improved coronary artery diameter and less intimal thickening. Antihypertensive therapy is usually completed by diuretics. Beta-blockers should not be used as they hamper the already delayed chronotropic response of the denervated heart.

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.

Issues Related to Clinical Studies of Chemoprevention

A clear precondition of chemoprevention is negligible toxicity of the agent. Toxicity is of special concerns to older individuals who are more subject to adverse effects of drugs due to altered pharmacokinetics, reduced functional reserve of organ and systems, and increased risk of drug interactions 1. Toxicity is a concern with available agents. Even at low doses, cis-retinoic acid is considered too toxic for routine prevention of cancer of the upper digestive and respiratory tract 51. Tamoxifen increased threefold the risk of endometrial cancer and twofold that of cerebrovascular

Transferred NOE Spectroscopy

The binding of molecules to receptors is an equilibrium process in which there is chemical exchange between the free and bound forms of the ligand. Exchange results in the drug adopting the different physical properties of the receptor with attendent alterations in the correlation times and effective masses of the drugs. During the drug's residence in its receptor-binding site, it will adopt the bound configuration, which may bring remote groups into proximity. The resulting intramolecular NOEs in the NMR spectrum will give useful information about the distances between these groups in the bound state. Chemical exchange with drug molecules free in solution will transfer the bound NOE from the bound drug to the free drug, resulting in a trNOE. Protein-drug interactions cause significant relaxation enhancement even when the drug concentration is in excess by 10- to 100-fold over that of the receptor. In this way, the trNOE is amplified and visible in the narrow resonances of the drug in...

Market Drivers And Commercial Prospects

Furthermore, protein microarrays will permit researchers routinely to study families of proteins in their efforts to understand the complex interactions of protein systems inside cells. Such studies can illustrate protein interactions and signaling pathways, providing more definite answers to whether a potential target is indeed involved in the disease etiology and how it affects the disease development. Scientists can address more complicated questions about gene function and drug interactions than they otherwise might.

Effects of Current Therapy of Chronic Viral Hepatitis on Drug Metabolism

IFN-a and other type-1 IFNs have been shown to affect phase I drug metabolism, potentially increasing the risk of adverse drug interactions. Not unexpectedly, these effects depend on the particular isoenzyme of cytochrome P-450 that is under consideration. Horsmans et al. (21) investigated the effect of IFN-a on the cytochrome P-450-mediated metabolism of 14C-aminopyrine, in patients with CHC. They found a In a recent study, Pageaux et al. (23) studied the effects of IFN-a on in vivo caffeine metabolism (as a measure of CYP1A2 activity) and in vivo cortisol metabolism (as a measure of CYP3A activity) in patients with CHC. They found no significant changes in either of these activities, and concluded that drugs that are metabolized by these isoenzymes can be used together with IFN-a, without a significant risk of adverse drug interactions. There have been a number of reported examples of IFN-drug interactions. Treatment with IFN-a was reported to potentiate the anticoagulant effects of...

Structure Activity Relationship From the many series of azoles that have been re

My721 Huntsman

As a class, the azoles are notable for their propensity for drug-drug interactions. Most have measurable affinity for human CyP450 enzymes. Interactions of ketoconazole with other agents, however, are much more frequent than with newer compounds, especially fluconazole. Compounds such as rifampicin increase ketoconazole clearance through the induction of hepatic enzymes. The types of drug interactions observed with fluconazole are generally similar to those of ketoconazole or itraconazole. but the number and severity of relevant interactions reported with fluconazole are much lower than those with the other two agents.

Neuropsychiatric Manifestations

The selective serotonin reuptake inhibitors (SSRIs) are the antidepressants of choice for treating IFN-induced depression. First, these agents appear to be well-tolerated and safe in patients with liver disease. Fluoxetine has a positive impact on the mental slowing associated with IFN, and venlafaxine and buproprion have stimulating effects that also help the mental slowing associated with IFN. Sertraline is easy to titrate, and very safe in liver disease, and citalopram has minimal drug-drug interactions. The clinician should become familiar with one or two the SSRIs, and use these, once depression is diagnosed. Tricyclic antidepressants, with their anticholinergic activity, are not recommended, particularly for patients with cirrhosis, since they may exacerbate cognitive dysfunction. Counseling and psychiatric consultation are advisable for all patients with more than mild depression.

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...

Pharmacokinetic Features

Features of topotecan are very complex. The drug is subject to alteration by esterases and the products are variously glucuronidated as well as oxidized by CYP 3A4, so is subject to a number of possible drug-drug interactions (238). After oral administration, about 30-40 of the drug is bioavailable (239-241). After i.v. dosage of prodrug irinotecan, rapid metabolic conversion by hydrolysis of the carbamoyl moiety to an active phenolic metabolite (SN-38) occurs as a result of the action of liver carboxylesterase this is followed by glucuronidation to a metabolite that is much less potent. Metabolite SN-38 is about

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).

Pharmacology

Each of the regulatory agencies requires that the pharmacological properties of the compound be presented in three separate sections (1) primary pharmacology, which should discuss activity related to the proposed therapeutic use (2) secondary pharmacology, which should describe other activities and (3) drug interactions, which is required when relevant.

Pharmacogenetics

Pharmacogenetics and pharmacogenomics are emerging disciplines that focus on genetic determinants of drug response at the levels of single genes or the entire human genome, respectively (13). Polymorphisms may influence drug response in three ways (14). The first way is through pharmacokinetic interactions, caused by genetically based differences in drug absorption, disposition, metabolism and excretion. An important role is played by polymorphisms in the cytochrome P450 (CYP) enzymes. In addition, there are pharmacodynamic gene-drug interactions that involve gene products expressed as receptors or signal transduction molecules, which are relevant to the pharmacodynamics of drugs. After entering the circulation each drug interacts with numerous proteins and multiple types of receptors. These proteins determine the site of action and the pharmacological response. The third possibility of influencing drug response is through genes

Nmda

Oxcarbazepine or 10,11,dihydro-10-oxo carbamazepine, 12) was designed to avoid the dose-dependent side effects noted in some patients (e.g., nausea, headache, dizziness, ataxia, dip-lopia) and to minimize enzyme induction and drug-drug interactions displayed by carbam-azepine (195, 196). As shown previously (Fig. 6.3), the change in structure results in a difference in metabolism. Although both carbamazepine and oxcarbazepine are ultimately converted to the inactive trans diol, oxcarbazepine does not form the active 10,11-epoxide intermediate, but does form the active 10-hydroxy metabolite MHD (197).The mechanism of action of oxcarbazepine is very similar

Regulatory Issues

Side effects and drug interactions observed during the expanded-use study are required to be included in the package insert (which will generally increase the incidence of the side effect). By admitting patients who would be excluded from the controlled clinical study, the chance also exists that side effects and drug interactions that were not observed during the tightly controlled premarketing studies will be reported. These effects and interactions will require further characterization by the drug company and may need to be included in the package insert. In a severely ill population where the course of the disease is poorly understood, it may be difficult to ascribe causality to either drug or disease. A well-designed expanded-use protocol and study controls help to minimize the speculation that accompanies causality of adverse events during clinical trials.

Tuberculosis

And isoniazid, caused by the induction of citochrome P-450 system, may interfere with the metabolism of other drugs, metabolized through the same enzymatic pathway and the reverse can be true. In Table 16.5, the principal drug interactions of antituberculous drugs are indicated.

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

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....