Drug Interaction

Role of Transporters in Drug Interactions

Interactions involving drugs that have a low therapeutic index are the most clinically significant. These are discussed in Chapter 15 (Tables 15.1 and 15.2 list cytochrome P450 and P-gp and other transporter substrates, inhibitors, and inducers that may be involved in drug-drug interactions). As discussed there, it is noteworthy that many of the inducers of cytochrome P450 also induce drug transporters, and this induction may be mediated by the same regulatory systems e.g., pregnane X receptors (PXR) and the constitutive androstane receptor (CAR) . The growing use of herbal and other dietary supplements by the lay population suggests that an increase in dietary supplement-drug interactions may occur. For example, St. John's wort (Hypericum perforatum) was shown to decrease the digoxin AUC by 25 after 10 days of treatment (118). The effect appears to reflect induction of P-gp expression. Whether the active component leading to induction is the same or different from hypericin (one of...

Evaluating Drug Interactions

Rarely is a drug devoid of potential for drug interactions. A sound early clinical development program is used to assess such interaction potential, typically with drugs that are expected to be used concomitantly with the investigative drug, or with those that may have a significant effect on the pharmacokinetics of the drug (e.g. the effect of oral contraceptives on the pharmacokinetics of a drug that will be used by women of childbearing potential). After the drug is marketed, and more patients use the product under a multitude of conditions with a higher degree of concomitant medication use, the potential for drug interactions can be more fully assessed. Potential interactions are usually reported via the spontaneous reporting system, and can result in further evaluation in large Phase IV post-marketing safety surveillance trials. If a beneficial effect of concomitant medication use is anecdotally reported, such concomitant usage can be formally explored in a Phase IV clinical...

Prediction And Clinical Management Of Drug Interactions

In vitro systems are commonly employed to assess the potential for CYP and transport protein-mediated drug interactions. Microsomes, liver and kidney slices, isolated and cultured hepatocytes, membrane vesicles, and recombinant human DNA-transfected cells are all methods of determining the roles of metabolism and drug transport in drug interactions. Unfortunately, most in vitro methods are able to assess the potential for inhibition, but not induction. For inhibitors that also cause enzyme induction or influence multiple metabolic pathways, in vitro predictions may be markedly different from in vivo findings. Further, inhibitors that are identified by in vitro screening methods may be found to inhibit CYP enzymes or transport proteins only at exceedingly high concentrations. Since it is not always possible to predict the concentration of a drug or its metabolites at specific sites in vivo, it is often difficult to define the clinical significance of such findings. Predicting...

Hospital Admissions Studies

Note Numbers are percent of admissions as reported. X qualitative mention in report NStudies number of studies that mentioned a DTP in the group Avg. of Patients sum of percent mentions divided by 10. The original terms used in the individual studies were retained in most cases, abbreviated as follows DI drug interaction DP duplicate prescription (therapeutic duplication) DSE side effect of drug FP failure to receive prescribed drug ID inappropriate dose IF inadequate follow-up IMR immunological reaction IP inappropriate prescribing (including wrong directions) NC patient noncompliance or nonadherence OD excessive drug dosage TF treatment failure UI untreated indication UD underdosage WD wrong drug taken WI drug use without indication. Some terms may be synonymous, while others may have overlapping meanings. For example, various investigators have named an inappropriate drug order as inappropriate prescribing, contraindicated drug, wrong drug, duplication of therapy, and untreated...

Hplcmsms Quantitative Assays of Cytochrome P450 Enzyme Activity

Knowledge of potential drug-drug interactions has led to a need to assay specific cytochrome P450 (CYP) enzyme activities to determine whether new drug entities have inhibitory properties. Enzyme activity measurements require kinetic assays that will remain highly specific in the presence of the new drug entities that are being evaluated. That requirement led Walsky and Obach (8) to develop a panel of 12 validated LC MS MS assays for 10 of the human CYP enzymes most commonly involved in drug metabolism. The assay of CYP2B6 activity is described in some detail here because it illustrates the principles applied to the separation and analytical steps common to all of the assays. Each CYP enzyme can be distinguished by a

Nonprescription Drugs and Nutritional Supplements

Second, nonprescription drugs can cause toxicity, side effects, and drug interactions. Aspirin is sold OTC in practically every country, and other more potent drugs in its class are available OTC in most countries. These drugs can cause severe, even fatal, gastrointestinal bleeding. Aspirin affects blood coagulation and interacts with the anticoagulant effect of the prescription drug warfarin. Cimetidine is a safe enough drug to be sold OTC in the United States, but it can interact with a number of other OTC and prescription-only drugs. Perhaps they are OTC because their labeled indications are self-limiting.

Receptor Mediated Effects

Dose-effect curves are also useful for studying phar-macodynamic drug interactions (Figure 18.5B). A competitive antagonist binds to the same binding site as does the agonist, and the competitive antagonist can be displaced from the binding site by an excess of the agonist. Therefore, the maximum effect of an agonist can still be achieved in the presence of a competitive antagonist, if a sufficient dose or concentration of the

Prescribing And Adverse Events

This new potential for adverse drug interaction is enormous. NSAIDs and aspirin interact with anticoagulants such as warfarin or coumadin, can increase the bleeding tendency, and not just from the stomach. Antacids can decrease the excretion of antidepressant tricyclics, quinidine, pseudoephi-drine and indomethacin. They can also reduce the absorption of digoxin and -blocker hypertensive medication. These are only a few of the multitude of interactive drug effects. This is imposed upon the reduced efficacy of hepatic metabolism and elimination, and renal excretion in the elderly thus, drug OTC use can add to the recipe for toxic drug accumulation and, in the latter case of antacids, cause further damage to the kidney by loss of blood pressure control and worsening cardiac failure.

Overview Of International Harmonization Conference Guidelines

Drug interaction studies should be done on digoxin and oral anticoagulants, for these drugs have a narrow therapeutic range and are commonly prescribed in the elderly. These drugs frequently have their serum levels altered by other drugs. Where drugs are heavily metabolized by the liver, the effect of drug enzyme inducers and inhibitors should be explored. Similarly, drugs which will share the same cytochrome P450 enzyme pathways should be tested. Ketoconazole, macrolides, and quini- dine are given as examples. Finally, other common drugs most likely to be used with the test drug are recommended to be explored for possible synergis-tic or antagonistic drug interactions.

Drug Metabolism Interactions of Particular Importance to Women

Women use herbal and dietary supplements at higher rates than men do. This rise in use of alternative therapies places women at increased risk of significant drug interactions, specifically drug-herb and drug-nutrient interactions (83-89). For instance, St. John's wort, a popular antidepressant, contains at least seven groups of chemical compounds. These include naphthodianthrons (hypericin and pseudohy-pericin), flavonoids (quercetin, hyperoside, and rutin),

Pxrsxr Steroid and Xenobiotic Signaling Pathways

Human PXR (hPXR) or SXR is also activated by a large number of steroid agonists and antagonists such as estrogen and tamoxifen, drugs such as rifam-picin and nifedipine, xenobiotic compounds, and dietary bioactive compounds such as phytoestrogens. Many of these compounds induce the catabolic CYP450 enzymes including CYP3A4, which metabolize a number of steroids and xenobiotics including 60 of clinically relevant drugs in humans. Rifampi-cin is involved in drug-drug interactions by inducing CYP3A4 and altering the metabolism of other drugs. Long-term administration of rifampicin to patients with tuberculosis leads to increased steroid clearance. This can, in some cases, lead to misdiagnosis of Cush-ing's syndrome owing to an increase in urinary steroid levels. Steroid levels return to normal when the drug is withdrawn. In patients with Addison's disease, who mainly lack the ability to synthesize adrenal steroids, administration of rifampicin leads to a rapid depletion of endogenous...

Pharmacogenetics in solid organ transplantation

Recognized that different transplant recipients respond in different ways to immunosuppressive medication (Zheng et al., 2005). The inter-individual variations are greater than the intra-individual variations, a finding consistent with the notion that inheritance is a determinant of drug responses. In the general population, it is estimated that genetics accounts for 20 to 95 of the variability in drug disposition and effects (Kalow et al., 1998). Many other non-genetic factors, such as organ function, drug interactions, and the nature of the disease, probably influence the effects of medication. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in the inter-individual variability of the pharmacoki-netic or pharmacodynamic characteristics of immunosuppressive drugs, major side effects, and immunologic risks. The promising role of pharma-cogenetics and pharmacogenomics in...

Critical Drug Development Paradigms

A PI includes the following information Who should receive the new drug How much drug should be given How frequently should the drug be given For how long does the drug need to be given to be effective And, of course, the PI must include much additional important prescribing information regarding drug-drug interactions, the effect of the patient's age on the drug's activity, how to administer the drug, potential adverse effects of which the prescriber and patient need to be aware, and the contraindications, precautions, and warnings. One way to remember the label-driven question-based drug development concept is to think We sell only the package insert, we give away the product Indeed, the starting point for the development of a clinical plan to demonstrate the differentiation of a new drug could be the creation of a spreadsheet, with the rows consisting of all drugs (marketed and in development) for the same or similar indications. The spreadsheet columns might include indications,...

Learning Contemporary Clinical Drug Development

Drug-Drug Interactions Revised Labeling and Removal from the Market The calcium channel blocker mibefradil (Posicor ) was removed from the market in 1998. The headline for the Pink Sheets article describing this action was Posicor Withdrawal Reflects 'Complexity' of Interaction Profile (59). Products identified as potentially dangerous in combination with mibefradil included cardiac drugs, such as amiodarone, flecainide, and propafenone oncologic products, such as tamoxifen, cyclophosphamide, etoposide, ifosfamide, and vin-blastine and the immunosuppressant medications cyclosporine and tacrolimus. The sponsor's decision to withdraw mibefradil was based on the complexity of the drug interaction information that would have to be communicated to ensure safe usage.

Strategic Considerations for Orally Administered Solubility Prodrugs

Drug-drug interaction potential, or toxicity. A phosphate prodrug is not expected to alter the distribution, systemic elimination, or side effects of a drug, since the parent drug is liberated at or near the apical membrane in the GI lumen. Thus, a parent drug with high metabolic clearance or extraction ratio is often a poor choice for a soluble prodrug. Even with a fraction absorbed (Fabs) near 1, a drug can still be poorly bioavailable due to significant first-pass elimination because the maximum achievable bioavailability (Fmax) is a function of clearance (CL) and liver blood flow (Q), according to Eq. 5 (Kwon, 2001 Ward et al., 2001).

Additional Effects On Drug Metabolism

The effect of repeated doses of a drug, or of another drug or dietary or environmental constituent on that drug, may be to enhance or inhibit the metabolism of the drug. Both enzyme induction and inhibition are important causes of drug interactions (Chapter 15). Phenobarbital is prototypical of one general type of inducer polycyclic aromatic hydrocarbons are representative of another class that affects different CYPs. The mechanism for environmental and drug induction of CYPs involves the intermediacy of ligand-regulated FIGURE 11.4 Mechanistic basis of enzyme induction resulting from drug-drug interactions. The orphan nuclear pregnane X receptor (PXR) is a transcription factor that forms a heterodimer with the nuclear retinoid X receptor (RXR) to regulate expression of the CYP3A gene. Drug A binds to PXR and induces expression of the CYP3A enzyme, thereby accelerating metabolism of drug B. (Reproduced with permission from Wilson TM, Kliewer SA. Nat Rev Drug Discov 2002 1 259-66.)...

Detection Of Enzyme Induction

Iproniazid Medicine

In contrast to enzyme induction, inhibition usually only requires a single dose or exposure. Although environmentally it may be of less consequence than induction, with drug interactions it is probably of greater importance. Many of the different enzymes involved in the metabolism of foreign compounds may be inhibited with consequences for the biological activity of those compounds. As with enzyme induction, the consequences of inhibition will depend on the role of metabolism in the mechanism of toxicity or other biological activity. Thus, enzyme inhibition may increase or decrease toxicity or cause no change. and is metabolized to a reactive carbene which binds to the enzyme. It may also inhibit 8-aminolaevulinic acid synthetase, the rate-limiting step in haem biosynthesis. It is used as an insecticide synergist (see Chapter 2) to block the microsomal enzymemediated metabolism of insecticides. For example, when a structurally similar synergist, 2,3-methylenedioxynaphthalene, is mixed...

Role of Transporters in Drug Absorption

Competition between substrates for limiting transporter molecules and other effects lead to drug-drug, drug-food, and drug-dietary supplement interactions very similar to those seen with CYP450s. In an explicit test of GI absorption exsorption interactions, small intestinal secretion of intravenously infused tal-inolol, a b1-adrenergic receptor antagonist, has been studied in healthy volunteers using a steady-state perfusion technique (88). Perfusion of dexverapamil (-R)-verapamil into the intestinal lumen lowered the intestinal secretion of talinolol 29-56 . The conclusion is that bioavailability of talinolol is in part limited by exsorption and may be subject to drug interactions during absorption. In this study (_R)-verapamil was used because it is known to affect P-gp-mediated drug transport, but is devoid of the pharmacological effects of (S)-verapamil. Hence, it can be used safely as a probe in clinical studies of P-gp inhibition. P-gp can be activated as well as inhibited, as...

Medication Use Process

Dispensing Drug Process Diagram

Medications are prescribed, distributed, and consumed under the assumption that the therapeutic plan will work as intended to provide the expected outcome. It is clear from previous chapters that there are many biological system issues that will influence success of the plan. Other organizational and societal system issues also influence success of the therapeutic plan as profoundly as do the biological systems issues. A prescriber writes an order for a medication based on the best available information, the likely diagnosis, and the expected outcome. A pharmacist reviews the requested medication order (prescription), clarifies it based upon additional information about the patient or medication (allergies, drug interactions, etc.), prepares the medication for use, counsels the patient about the drug, and gives it to the patient. The patient is responsible for understanding the therapeutic objective, knowing about the drug, creating a daily compliance plan (deciding when to take the...

Mechanisms of Renal Handling of Drugs

Competition by drugs for renal tubular secretion is an important cause of drug-drug interactions. Inhibitors of P-glycoprotein slow this renal tubular pathway. Anionic drugs compete with other anionic drugs for these active transport pathways, as do cationic drugs for their pathways. When two drugs secreted by the same pathway are given together, the renal clearance of each will be less than when either drug is given alone. Methotrexate is a clinically important example of an anionic drug that is actively secreted by renal tubular cells. Its renal clearance is halved when salicylate is coadministered with it (17).

Analysis and Prevention of Medication Errors

Given the latent errors associated with some elements of human performance, it seems likely that automation may reduce error. Several studies have demonstrated the value of computer assistance in the medication order entry process. Rules-based physician order systems have been shown to identify and reduce the chances of adverse medication events due to drug duplication, calculation errors, and drug-drug interactions (25, 27-30). Despite these demonstrated advantages to computer-assisted medication ordering, the process is still far from error free. Med-MARx data from 2003 showed that nearly 20 of the medication errors reported to that national database were associated with problems in computerization and automation (31). A large number of these were order entry errors associated with interruptions during order entry. Another study showed that an early-generation computerized prescriber order entry system facilitated some error types due to formatting and display limitations (32). In...

Restrictively Metabolized Drugs ER

It usually is assumed that the free drug concentration in blood is equal to the drug concentration to which hepatic drug-metabolizing enzymes are exposed. Although protein binding would not be anticipated to change hepatic clearance significantly for restrictively metabolized drugs that have fu 80 , displacement of highly bound (fu 20 ) drugs from their plasma protein binding sites will result in a significant increase in their hepatic clearance. However, steady-state concentrations of unbound drug will be unchanged as long as there is no change in CLint . This occurs in some drug interactions, as diagrammed in Figure 7.2. This situation also is encountered in pathological conditions in which plasma proteins or plasma protein binding is decreased, as described in Chapter 5 for phenytoin kinetics in patients with impaired renal function. Since pharmacological effects

Cosme Manzarbeitia Michael K McGuire and Rohit Moghe

Rohit Such Anti Body

The goal of immunosuppression in transplant patients is to prevent acute and chronic rejection of the transplanted organ, while avoiding opportunistic infections and the adverse effects of immunosuppressive therapy (see Fig. 17.1). Combinations of immunosuppressants are used to affect different immune-system activators and to provide immunosuppressive synergy, using the lowest effective doses of immunosuppressants to reduce the potential for adverse drug events and drug interactions. Superiority of one regimen over another has not been demonstrated, and immunosuppressive protocols are largely program-specific. Familiarity with the immunosuppressants used in a particular programs' protocol is critical, along with a concordant understanding of therapeutic drug monitoring through serum levels and graft evaluation, adverse drug reaction monitoring, and judicious use of auxiliary medications that prevent and treat the consequences of immunosuppression. However, regimens should be flexible...

Case Method Analysis of the Drug Discovery Process Using External Imaging

Framework for analyzing examples of actual business decisions and, from that, obtaining insight into the process 4 . Several conferences have addressed the use of imaging in drug research and development, but none, in our experience, had analyzed decisions made during the drug development process based on collaborative imaging studies. Nuclear Medicine imaging techniques were used in the eleven case method presentations. The special issue reporting on this conference contains descriptions of pre-clinical studies in knockout mice, pre-clinical PET studies in non-human primates, a series of Phase I studies (dosing studies, pharmacokinetics unique delivery systems , dose, dose interval, drug interactions), Phase I II (dose response, response duration, pharmacokinetic pharmacodynamic

Chimeras Of P450 Enzymes

The production of catalytically self-sufficient P450 enzymes in bacterial hosts has a wide range of possible exciting applications. For instance cytochromes P450 metabolise a range of drugs and chemicals so bacteria containing these enzymes may help to further our understanding of human drug metabolism, the consequences of drug-drug interactions and the activation of carcinogens. The fusion protein hosts may also allow the mass production of compounds of interest by incorporating P450 biosynthetic pathways into one or a variety of hosts. Another application maybe the breakdown of environmental toxins, many of which are P450 substrates. The proteins may also further our understanding of the effect of P450 polymorphisms on human health by The most important human drug metabolising enzyme CYP 3A4 has also been turned into a fusion protein 96 . The latter investigators fused the human CYP 3A4 to the CPR of Rat and used this protein to study the formation of metabolite-inhibitor complex...

Susceptibility to Infection

In many endemic areas, a medication to reduce the risk significantly, but never completely, should be taken. Some of these medications are metabolised at the cytochrome P450. Mefloquine is a good example. Drug interaction should thus be a concern. Other drugs may contain a medication the HIV-infected person is already taking, at a different dose. For example, Malarone contains atovaquone. Other medications could be used with acceptable efficacy for individuals with an already complicated therapy or those who have experienced severe side-effects with previous changes in regimens. Azithromycin, rarely used in practice because of limited efficacy, and primarily cost, is an example. Doxycycline, increasingly used for chloroquine-resistant areas, can increase the risk of photosensitivity or of a recurrence of candidiasis.

Polymer Cushioned Bilayer Lipid Membranes

The hybrid bilayer membranes, BLMs from direct fusion of vesicles and the MillerNelson films have already qualified for investigations of cellular immune responses, specific receptor-ligand bindings and various membrane interactions. Peripheral proteins or membrane proteins that are not spanning the whole membrane are also suitable for investigations in these simpler systems. In the near future much is expected to merge from these approaches, for instance in pharmaceutical approaches such as drug interaction with a biomembrane surface.

Components Of Preclinical Drug Development

In vitro methods may also have utility for predicting important pharmacokinetic parameters, such as oral absorption and hepatic metabolism. For example, oral bioavailability can be predicted by measuring drug transport across a monolayer of Caco-2 human colon carcinoma cells, as discussed in Chapter 4 (9, 10). Specific pathways of potential importance for drug metabolism and elimination can be explored using well-defined drug-metabolizing enzyme systems (11, 12). When coupled with sensitive qualitative analytical methods, such studies can identify metabolites that may be searched for in vivo. Furthermore, these studies can also identify potentially relevant drug interactions arising from competition for common drug-metabolizing enzymes, such as CYP3A4 (12). Finally, in vitro protein binding studies prior to in vivo testing can provide early information as the extent of distribution of a novel agent and can help interpret the free and bound concentrations observed in pharmacokinetic...

Postoperative Period

Patients in the postoperative period can develop psychiatric symptoms because of the stress of hospitalization, the disappointment of an outcome that is not what was expected, or a recurrence of an underlying psychiatric disorder. Patients who develop depressive or anxiety syndromes should be treated, if at all possible. However, patients may not require pharmacologic treatment simply for a brief period of distress. For example, a day or two of crying and distress may be perfectly normal and would not require an antidepressant. Decisions regarding the initiation of treatment should be made in conjunction with the psychiatric consultant. A major depressive disorder should not be diagnosed without the depressed mood being experienced most of the day, every day for 2 weeks. If the transplant patient requires psychotropic medication, caution should be exercised. Most psychotropic medications are metabolized in the liver, the exceptions being lithium and gabapentin. They are excreted by...

Epidemiology

It is widely recognized that the risk of developing an adverse drug reaction (ADR) secondary to a drug-drug interaction increases significantly with the number of medications a patient is receiving. Adverse drug reactions are estimated to be responsible for 4.2-6 of all hospital admissions in the United States (3). Reports on the incidence of drug interactions vary widely, with estimates as high as 50 (4). Data from older studies tend to overestimate the frequency by including clinically insignificant and theoretical interactions. The true incidence of clinically significant ADRs that occur as a result of drug-drug interactions is largely unknown. Further, the frequency and significance of drug interactions vary considerably among different patient populations. HIV patients, for instance, are at greater risk for developing adverse reactions due to drug interactions because of the nature and quantity of medications they are on, as well as the pathophysi-ology of their disease state (5,...

Induction

Despite having 10-50 less CYP3A content than is found in the liver, the gut remains an important site for many drug interactions (54). Fura-nocoumarins in grapefruit juice, for instance, both reversibly and irreversibly inhibit CYP3A4 in the small intestine (55). As a result, grapefruit juice significantly increases the bioavailability of a number of CYP3A4 substrates, including cyclosporine, saquinavir, mida-zolam, calcium channel blockers, terfenadine, and certain hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors (55-61). Other drugs that significantly alter intestinal CYP3A4 metabolism include ketoconazole, itraconazole, erythromycin, cyclosporine, and verapamil (54). CYP3A4 inhibition often occurs in conjunction with P-glycoprotein (P-gp) inhibition in the gut, complicating estimates of the relative contribution of gut wall metabolism to drug interactions (see Chapter 4, Table 4.2). The rifamycins are well known for their potent and relatively nonspecific induction...

Conclusion

The dose- or concentration-effect relationship is a central tenet of pharmacology. Dose-effect studies contribute to our understanding of the site of action of a drug, the selection of a dose and dosing schedule, the determination of an agent's potency and efficacy, and the elucidation of drug interactions. An essential aspect of the preclinical and clinical evaluations of any new drug is the careful delineation of the dose-effect relationship over the anticipated dosing range for the drug's therapeutic and toxic effects. More rational individualized dosing regimens that incorporate adaptive dosing, therapeutic drug monitoring, and the determination of risk benefit from therapeutic indices have evolved from the integration of our knowledge of pharmacokinetics and pharmacodynamics.

Regulatory Response

As a result of this, and the fact that 30 of prescription drugs by then were consumed by just 12 of the population (those over 65 years), a new guideline was issued. Thus, the FDA Guideline on Drug Development in the Elderly (1990) recommended that, if a drug was likely to have significant use in the elderly, then studies should be done in an elderly population. These studies should look at effectiveness and adverse events by age. In addition, other studies should determine whether older people handle the new drug differently (a 30 decrease in renal excretion and liver metabolism is normal in a healthy elderly person). This guideline also required studies of the pharmacokinetics and, where possible, pharmacodynamic studies of the new drug in the elderly. The Guideline also urged the study of possible drug interactions with drugs commonly used concurrently in this age group. Digoxin was given as an example. Looking even further forward to the future, the...

Classification

The classification of Rawlins and Thompson is perhaps the most widely used to describe adverse drug reactions (19). Although this classification system continues to evolve, it serves a useful purpose. Adverse reactions are categorized as Type A or B. Type A reactions are those that extend directly from a drug's pharmacological effects. They are often predictable and dose dependent and may account for up to two-thirds of all ADRs. Type A reactions also include adverse effects resulting from drug overdose and drug-drug interactions. Sedation caused by an antihistamine and hypotension caused by a b-adrenergic antagonist are considered Type A reactions. Type B reactions are idiosyncratic or immunologic reactions that are often rare and unpredictable. Examples of Type B reactions include aplastic anemia caused by chloramphenicol or rash induced by b-lactam antibiotics. Albeit not universally accepted, other authors have extended this classification system to include Types C, D, and E...

Risk Factors

Concurrent use of multiple medications is another major ADR risk factor. The potential for clinically significant drug interactions and additive adverse effects increases as the number of medications in a regimen increases (28, 29). In a study of over 9000 hospital admissions, the strongest predictor of ADRs was the Genetic differences can also influence the likelihood of some drug interactions. For example, coad-ministration of the antiarrhythmic propafenone to patients being treated with metoprolol substantially reduces metoprolol metabolic clearance in extensive

Clinical Evaluation

Because of the importance of drug interactions (see Chapter 15), a detailed medication history should be recorded that identifies all prescription, nonpre-scription, and alternative or complementary medications used by the patient. In addition to medication dosage, other factors that may contribute to the development of adverse reactions include medication administration route, method, site, schedule, rate, and duration. A history of allergies, intolerances, and other medication reactions should be fully investigated. The potential for cross-allergenicity or cross-reactivity should not be overlooked. The possibility of drug-induced laboratory test interference (analytical or physiological) and drug-drug or drug-nutrient interactions should also be explored.

Toxicity

In vitro toxicity assays date back more than two decades to the introduction of Ames testing for muta-genicity and carcinogenicity. More recently, an in vitro test for clastinogenicity has become accepted as a reliable predictor of in vivo chromosome breakage. In vitro tests described above for metabolism studies, such as microsome fractions or hepatocyte cultures, can prove useful for identifying metabolic pathways, such as cytochrome P450s, and indicate the possibility of potential drug-drug interactions. Of course, all such in vitro tests should be performed with human proteins, cells, or tissue samples, as species differences can play an important role in toxicity. Despite all these new tests, adequate in vitro tests for such common critical toxicity issues as hepatotoxicity, do not exist as yet and would be of great value in helping to eliminate unsuitable compounds early in preclini-cal development.