Clearance by Continuous Hemofiltration

Hemofiltration removes solutes by convective mass transfer down a hydrostatic pressure gradient (17, 18). As plasma water passes through the hemofilter membrane, solute is carried along by solvent drag. Convective mass transfer thus mimics the process of glomerular filtration. The pores of hemofilter membranes are larger than those of dialysis membranes and permit passage of solutes having a molecular weight of up to 50 kDa. Accordingly, a wider range of compounds will be removed by...

Plasma Protein Binding of Basic and Neutral Drugs

The protein binding of basic drugs tends to be normal or only slightly reduced (25). In some cases, this may reflect the facts that these drugs bind to a1-acid glycoprotein and that concentrations of this glycopro-tein are higher in hemodialysis-dependent patients than in patients with normal renal function. The bioavailability of most drugs that have been studied has not been found to be altered in patients with impaired renal function. However, the absorption of d-xylose, a marker compound...

Cyp2c11

And enzyme activity, and is due primarily to a down-regulation of CYP gene transcription, but modulation of RNA and enzyme inhibition may also be involved (58, 59). As shown in Table 32.14, the expression of CYP2C11 and CYP2D isoenzymes is frequently suppressed by cytokines. These two CYP gene families are consti-tutively expressed in male and female rats. In the rat, CYP2C is under developmental and pituitary hormone regulation. Although there is approximately 70 cDNA-deduced amino acid...

Clinical Consequences Of Different Drug Distribution Patterns

As pointed out in Chapter 2, the process of drug distribution can account for both the slow onset of pharmacologic effect of some drugs (e.g., digoxin) and the termination of pharmacologic effect after bolus intravenous injection of others (e.g., lidocaine and thiopental). When theophylline was introduced in the 1930s, it was often administered by rapid intravenous injection to asthmatic patients. It was only after several fatalities were reported that the current practice was adopted of...

Ch3conhnhcoch3

FIGURE 16.6 Metabolism of isoniazid to hydrazine, which is then activated by cytochrome P450 enzymes to a chemically reactive metabolite. N-Acetyltransferase (NAT2) acts at several points in this scheme to reduce hydrazine concentrations. This accounts for the fact that rapid acetylators are less likely than slow acetylators to develop isoniazid-induced hepatitis. On the other hand, chronic alcohol consumption induces cytochrome P450 enzymes, thereby increasing the extent of toxic metabolite...

Passive Diffusion

Passive diffusion is the transport of a molecule across a lipid bilayer membrane according to its electrochemical potential gradient without the assistance of additional transporter molecules. This process can be studied in pure lipid membranes, although it is acknowledged that the properties of even relatively pure lipid patches in native membranes are altered by the high density of neighboring protein molecules. The physical and functional properties of membranes can be modeled with varying...

Pgp Inhibition as an Adjunct to Treating Chemotherapy Resistant Cancers

Recognition of the importance of drug resistance efflux pumps has motivated a number of attempts to improve drug therapy by specific coadministration of P-gp inhibitors. Inhibition of P-gp or of its enhanced transcription in tumors may be a component in the anticancer activities of some agents such as ecteinascide 743 (ET-743) (120). Since the therapeutic index of verapamil, cyclosporine, and other marketed P-gp inhibitors is too narrow, dexverapamil and val-spodar are among a number of new...

Mechanisms Of Drug Interactions

Interactions Affecting Drug Absorption Interactions affecting drug absorption may result in changes in the rate of absorption, the extent of absorption, or a combination of both. Interactions resulting in a reduced rate of absorption are not typically clinically important for maintenance medications, as long as the total amount of drug absorbed is not affected. On the other hand, for acutely administered medications, such as sedative-hypnotics or analgesics, a reduction in the rate of...

Chronic Liver Disease and Cirrhosis

Chronic liver disease is usually secondary to chronic alcohol abuse or chronic viral hepatitis. Alcoholic liver disease is most common and begins with the accumulation of fat vacuoles within hepatocytes and hepatic enlargement. There is a decrease in cytochrome P450 content per weight of tissue, but this is compensated for by the increase in liver size so that drug metabolism is not impaired (18). Alcoholic fatty liver may be accompanied or followed by alcoholic hepatitis, in which hepatocyte...

Tissue Binding of Drugs

The distribution volume of some drugs also can be altered when renal function is impaired. As described in Chapter 3, Sheiner et al. (27) have shown that impaired renal function is associated with a decrease in digoxin distribution volume that is described by the following equation This presumably reflects a reduction in tissue levels of Na K-ATPase, an enzyme that represents a major tissue-binding site for digoxin (28). In other cases in which distribution volume is decreased in patients with...

Druginduced Liver Toxicity

Few areas have been as confusing to clinicians as is the perplexing array of adverse drug reactions affecting the liver. Given the central role that the liver plays in drug metabolism, it is not surprising that many drugs are converted to compounds that cause liver damage. In fact, liver injury has been estimated to be the principal safety reason for terminating clinical trials during drug development and for withdrawing marketed drugs (9). Traditional classifications of drug hepatotoxicity,...

Mutations That Influence Drug Receptors

P2-Adrenoreceptor Mutations in Asthma Since the first descriptions of genetic polymorphisms in the P2 receptor that may play a pathogenic role in the development of asthma (83, 84), a number of investigators have shown an association between these mutations and patient response to treatment for this disease. A number of missense mutations within the coding region of the type 2 P-receptor gene on chromosome 5q31 have been identified in humans. In studies utilizing site-directed mutagenesis and...

Project Planning And Management Tools

Several tools that are useful in the planning and management of biopharmaceutical projects are identified in Table 27.8. Definitions can be found in the Project Management Institute's (PMI) A Guide to the Project Management Body of Knowledge (5) and within the tutorial and help sections of Microsoft Project . TABLE 27.8 Project Planning and Management Tools Decision trees Milestone charts PERT charts Gantt charts Work breakdown structures Financial tracking It is important to point out that...

Oh

Tienilic Acid

FIGURE 16.7 Oxidation of halothane by CYP2E1 leads to formation of trifluoroacetyl chloride, which can be nonenzymatically converted to trifluoroacetic acid, can be scavenged by glutathione, or can bind covalently to tissue macromolecules, thereby causing liver damage. A reductive metabolic pathway generates free radicals that cause lipid peroxidation, but this pathway does not appear to be involved in the pathogenesis of halothane hepatitis. FIGURE 16.7 Oxidation of halothane by CYP2E1 leads...

Pharmacokinetic Consequences of Liver Cirrhosis

The net result of chronic hepatic disease that leads to cirrhosis is that pathophysiologic alterations may result in both decreased hepatocyte function, with as much as a 50 decrease in cytochrome P450 content, and or shunting of blood away from optimally functioning hepatocytes. Accordingly, cirrhosis affects drug metabolism more than does any other form of liver disease. In fact, cirrhosis may decrease the clearance of drugs that are nonrestrictively eliminated in subjects with normal liver...

Modification of Drug Therapy in Patients with Liver Disease

It is advisable to avoid using certain drugs in patients with advanced liver disease. For example, angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs should be avoided because of their potential to cause acute renal failure. Paradoxically, administration of captopril to cirrhotic patients with ascites actually impairs rather than promotes sodium excretion (58). Since coagulation disorders are common in patients with advanced cirrhosis, alternatives should be...

References

Yacobi A, Batra VK, Desjardins RE, Faulkner RD, Nicolau G, Pool WR, Shah A, Tonelli AP. Implementation of an effective pharmacokinetics research program in industry. In Yacobi A, Skelly JP, Shah VP, Benet LZ, eds. Integration of pharmacokinetics, phar-macodynamics, and toxicokinetics in rational drug development. New York Plenum 1993. p.125-35. 2. Peck CC. Rationale for the effective use of pharmacoki-netics and pharmacodynamics in early drug development. In Yacobi A, Skelly JP, Shah VP, Benet...

Effects Of Renal Disease On Drug Distribution

Impaired renal function is associated with important changes in the binding of some drugs to plasma proteins. In some cases the tissue binding of drugs is also affected. albumin binding sites by organic molecules that accumulate in uremia. As described in Chapter 3, reductions in the protein binding of acidic drugs result in increases in their distribution volume. In addition, the elimination clearance of restrictively eliminated drugs is increased. However, protein binding changes do not...

Patient Factors Affecting Hemodialysis of Drugs

Because elimination clearances are additive, total solute clearance during hemodialysis (CLt) can be expressed as the sum of dialysis clearance (CLd), and the patient's renal clearance (CLr) and nonrenal clearance (CLnr) When CLd is small relative to the sum of CLr and CLnr, hemodialysis can be expected to have little impact on the overall rate of drug removal. The extent of drug binding to plasma proteins is the most important patient factor affecting dialysis clearance, and in that sense...

Physiological Basis Of Multicompartmental Models Of Drug Distribution

Basis of Multicompartmental Structure In 1937, Teorell (12) first used a multicompartmental system to model the kinetics of drug distribution. The two body distribution compartments of his model consisted of a central compartment corresponding to intravascular space and a peripheral compartment representing nonmetabolizing body tissues. Drug elimination was modeled as proceeding from the central compartment. Drug transfer between compartments is characterized by intercompartmental clearance, a...

Drug Dosing Guidelines for Patients Requiring Renal Replacement Therapy

Drug doses need to be increased or supplemented for patients requiring renal replacement therapy only if CLEC, representing extracorporeal clearance from either intermittent hemodialysis or continuous renal replacement therapy, is substantial when compared to CLr + CLnr (Equation 6.12). Levy (34) has proposed that supplementation is needed only when CLEC is greater than 30 of CLr + CLnr. Several approaches will be considered that can be used to make appropriate drug dose adjustments for...

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...

Restrictively Metabolized Drugs ER

The product of fu and CLint is small relative to liver blood flow (usually about 1500 mL min) for drugs that are restrictively metabolized. Although the extraction ratio of these drugs is less than 0.3, hepatic metabolism often constitutes their principal pathway of elimination and they frequently have long elimination-phase half-lives (e.g., diazepam ti 2 43 hr). The hepatic clearance of these drugs is affected by changes in their binding to plasma proteins, by induction or inhibition of...

Analysis and Prevention of Medication Errors

Reason (21) has described a model for looking at human error that portrays a battle between the sources of error and the system-based defenses against them. This model is often referred to as the Swiss cheese model because the defenses against error are displayed as thin layers with holes that are described as latent error in the system. Figure 26.5 demonstrates the model as applied to medication error. Each opportunity for error is defended by the prescriber, pharmacist, nurse, and patient....

Mechanisms of Renal Handling of Drugs

Important mechanisms involved in the renal excretion and reabsorption of drugs have been reviewed by Reidenberg (15) and are shown in Table 5.1. Glomerular filtration affects all drugs of small molecular size and is restrictive in the sense that it is limited by drug binding to plasma proteins. On the other hand, renal tubular secretion is nonrestrictive since both protein-bound and free drug concentrations in plasma are available for elimination. In fact, the proximal renal tubular secretion...

Placental Transfer Of Drugs

The placenta was long thought to be a barrier to drugs and chemicals administered to the mother. However, the thalidomide tragedy, reported independently by McBride (75) and Lenz (76), showed that the placenta was capable of transferring drugs ingested by the mother to the fetus, with the potential for great harm. On the other hand, placental transfer of drugs administered to the mother has been used to treat fetal arrhythmias, congestive heart failure, and other conditions (77). The placenta...

Pq

FIGURE 25.1 Mechanisms of hypersensitivity reactions. Type I Antigens bind to antibodies on mast cells, causing degranulation and release of histamine and other mediators. Type II Antibodies attach to cell-surface antigens, causing activation of complement or other effector cells (neutrophils, K-lymphocytes, etc.), resulting in cell damage and cell death. Type III Antigen-antibody complexes are deposited in tissue. Type IV T-cells are sensitized to a specific antigen, thereby causing lymphokine...

Immunoaffinity Assays

Antibodies created by the immune response system can be powerful analytical reagents exhibiting unique specificity for molecular recognition. Antibodies are proteins that exhibit high affinity toward a specific aspect of an antigen, such as a particular amino acid sequence or chemical structure. The science of generating antibodies to low molecular weight drugs as antigens is highly advanced, beyond the scope of this chapter in general, however, drugs are covalently bound to multiple sites on a...

Project Planning And Management

Project planning and management for the biophar-maceutical industry began in the early 1980s and became an integral part of the R& D organization by the mid-1980s. The paper entitled Change + Communication Challenge Management of New Drug Development provides a review of the tools that are still used in biopharmaceutical project management (10). Project planning and management have progressed to the point that there are now six dimensions of project planning and management that are routinely...

Metabolic Ratio

FIGURE 13.5 Distribution of the debrisoquine MR in three genotype groups related to the CYP2D6*10 allele in 152 Korean individuals. Wild type (WT) CYP2D6*1 (or *2) and mutant (MUT) CYP2D6*10. (Reproduced with permission from Roh HK et al. Pharmacogenetics 1996 6 441-7.) Figure 13.5, the presence of this C188T mutation causes a rightward shift in the population of Koreans that was studied (29). The high frequency of this CYP2D6*10 allele is similar in Chinese, Japanese, and Koreans. Masimirembwa...

Carrier Mediated Transport Facilitated Diffusion and Active Transport

Several characteristics distinguish carrier-mediated transport from passive diffusion. Rates are generally faster than for passive diffusion, and transport is solute specific and shows a greater temperature variation (Q10). Transport is saturable, resembling Michaelis-Menten enzyme kinetics. Transport rates may not be the same in both directions across the membrane at a given substrate concentration. Transport may be inhibitable by competitive transport substrates or by noncompetitive...

Principles of Teratology

The principles of teratology have been articulated by Wilson (104). The first principle is that terato-gens act with specificity. A teratogen produces a specific abnormality or constellation of abnormalities. For example, thalidomide produces phocomelia, and valproic acid produces neural tube defects. This specificity also applies to species, because drug effects may be seen in one species and not in another. The best example is cortisol, which produces cleft palate in mice but not in humans....

Hematopoietic System and the Treatment of Cancer

Available data suggest that the antitumor therapeutic response of older patients is optimal when exposure to appropriate chemotherapy is the same as for younger patients. For example, the treatment of non-Hodgkin's lymphoma with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or etoposide, mitoxantrone, and prednimustine (VMP) is less effective in older patients when dose reductions are made (73, 74). Similarly, treatment of metastatic breast cancer in younger and older...

Medication Use Process

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...

Role of Transporters in Drug Absorption

As described in Chapter 4, oligopeptide and mono-carboxylic acid transporters facilitate the absorption of certain drugs. There have been a number of demonstrations that these natural transport pathways can be exploited to enhance drug action. An example demonstrating this concept is the discovery that valacyclovir is a substrate for the PEPT-1 transporter (81). Valacyclovir is an amino acid ester prodrug of the antiviral drug acyclovir. The usefulness of acyclovir is somewhat limited by its...

Physiokinetics Time Course Of Effects Due To Physiological Turnover Processes

In almost all cases, effects are mediated by an endogenous substance, and drugs modulate these effects indirectly by affecting either the production or elimination of this effect mediator (Figure 19.6). In addition to delays in drug effect due to pharmacoki-netic distribution to the site of action, there are delays determined by the turnover of these effect mediators. The time course of the physiological mediator can be thought of as an example of physiokinetics. Delays of a few minutes, or...

Info

This equation can easily be generalized for other exponents. Allometric principles may be used to answer a variety of questions relevant to the application of pre-clinical pharmacokinetic data to the design of dose regimens for humans. Two examples are the use of data from animals to estimate the human pharmacoki-netic parameters needed for selecting a starting dose for Phase I studies, and the design of intraperitoneal dose regimens for antineoplastic drugs. (rats, dogs, and monkeys) indicated...

Calculation of Dialysis Clearance

Currently, the efficiency of hemodialysis is expressed in terms of dialysis clearance. Dialysis clearance (CLd) is usually estimated from the Fick equation as follows where A is the solute concentration entering (arterial) and V is the solute concentration leaving (venous) the dialyzer. The terms in brackets collectively describe what is termed the extraction ratio (E). As a general principle, clearance from an eliminating organ can be thought of as the product of organ blood flow and...

Role of Transporters in Drug Distribution

Transporters are critical in the function of capillary endothelium, where they contribute to the blood-brain, blood-germinal epithelium (blood-testis and blood-ovary), and blood-placental barriers. Endothelial cells in each of these tissues express high levels of MDR-1. The existence of a blood-brain barrier is well established and is thought to arise from the formation of tight junctions between brain endothelial cells as well as the action of drug efflux pumps (91, 92). The importance of...

Phase I Biotransformations

Hemin Mechanism Drug

Liver Microsomal Cytochrome P450 Monooxygenases Among the major enzyme systems affecting drug metabolism, cytochrome P450 monooxygenases1 are dominant. In humans, there are 12 gene families of functionally related proteins comprising this group of enzymes. The cytochrome P450 enzymes, abbreviated CYPs (for cytochrome Ps) catalyze drug and endogenous compound oxidations in the liver, and also in the kidneys, gastrointestinal tract, skin, and lungs. Chemically, the processes of oxidation can be...

Therapeutic Response Cumulative Drug Effects And Schedule Dependence

Lasix Pharmacokinetics

So far we have focused our attention on the time course of drug effect. While the study of these effects can be helpful in understanding the mechanism of drug action and factors affecting efficacy and potency, it usually does not provide information on how drug exposure influences therapeutic response. Clinical response can be defined as the effect of drug treatment on the clinical endpoint of how the patient feels, functions, or survives. Some clinical responses can be described by composite...

Multifacilitator Superfamily Transporters

The nucleotide transporter (NT) family is illustrative of the multifacilitator superfamily (60, 61). Both naturally occurring nucleosides and most nucleo-side drugs are very hydrophilic and do not readily cross bilayer membranes except by mediated or active transport. The relevant transport activities have been defined functionally by their substrates, cosubstrates, and inhibitor sensitivities. Currently known nucleoside transport activities are either equi-librative or concentrative. The...

Effects of Liver Disease on the Renal Elimination of Drugs

Drug therapy in patients with advanced cirrhosis is further complicated by the fact that renal blood flow and glomerular filtration rate are frequently depressed in these patients in the absence of other known causes of renal failure. This condition, termed the hepatorenal syndrome, occurs in a setting of vasodilation of the splanchnic circulation that results in underfilling of the systemic circulation. This activates pressor responses, causing marked vasoconstriction of the renal circulation...

Age Related Changes in Hepatic and Extrahepatic Drug Biotransformations

Drug biotransformations occur in quantitatively important amounts in the liver, gastrointestinal tract, kidneys, lung, and skin. However, nearly all organs have some metabolic activity. As described in Chapter 11, in vivo drug biotransformations are commonly separated into Phase I and Phase II biotransformations. Phase I biotransformations are catalyzed by membrane-bound enzymes found in the endo-plasmic reticulum and Phase II biotransformations occur predominantly in the cytosol, with the...

Population Pharmacokinetics

Population pharmacokinetic parameters quantify population mean kinetics, between-subject variability intersubject variability , and residual variability. Residual variability includes within-subject variability, model misspecification, and measurement error. This information is necessary to design a dosage regimen for a drug. If all patients were identical, the same dose would be appropriate for all. However, since FIGURE 10.1 Fit obtained using a one-compartment model see Equation 10.6 to fit...

Pharmacokinetics in Patients Requiring Renal Replacement Therapy

ATKINSON, JR.1 AND GREGORY M. SUSLA2 i Clinical Center, National Institutes of Health, Bethesda, Maryland, 2VHA Consulting Services, Frederick, Maryland Although measurements of drug recovery in the urine enable reasonable characterization of the renal clearance of most drugs, analysis of drug elimination by the liver is hampered by the types of measurements that can be made in routine clinical studies. Hemodialysis and hemofiltration are considered at this point in the text because...

Effects of Renal Disease on Pharmacokinetics

ATKINSON, JR.1 AND MARCUS M. REIDENBERG 2 1 Clinical Center, National Institutes of Health, Bethesda, Maryland 2 Weill Medical College of Cornell University, New York, New York A 67-year-old man had been functionally anephric, requiring outpatient hemodialysis for several years. He was hospitalized for revision of his arteriovenous shunt and postoperatively complained of symptoms of gastroesophageal reflux. This complaint prompted institution of cimetidine therapy. In view of the...

Pharmacology Line Emission

FIGURE 12.12 Electrospray ionization mass spectra of bupropion solid line and 2Hg hydroxy-bupropion dotted line . Note that the protonated molecular ions MH , respectively, at m z 256 and 262 exhibit characteristic chlorine isotope peaks that have 25 of the molecular ion intensity at m z 258 and 264, due to the relative natural abundance of 35Cl and 37Cl. This is reflected also in the MH -H2O ions at m z 238 and 244. Data provided by R.L. Walsky and R.S. Obach, Pfizer, New York, NY. FIGURE...

Study Problems

Select the one lettered answer or statement completion that is BEST. It may be helpful to carry out dimensional analysis by including units in your calculations. Answers are provided in Appendix II. 1. A 35-year-old woman is being treated with gen-tamicin for a urinary tract infection. The gentamicin plasma level is 4 xg mL shortly after initial intravenous administration of an 80-mg dose of this drug. The distribution volume of gentamicin is 2. A 58-year-old man is hospitalized in cardiac...

In Vitroin Vivo Correlation Of Hepatic Metabolism

The liver has been the focus of most drug metabolism studies. While there is extrahepatic metabolism of some drugs, which may be extensive in some cases, the liver is generally considered the dominant organ in drug metabolism. Since liver tissue can be obtained from most species, including humans, in vitro study of hepatic metabolism has been FIGURE 30.9 Complex Dedrick plot of data from Figure 30.8. symbols are the same as in Figure 30.8 . Reproduced with permission from Khor SP et al. Cancer...

Generating Diversity

Not every drug lead will become a successful drug. Geldanamycin, for example, produced unacceptable hepatotoxicity. The next-generation derivative, 17-allylaminogeldanamycin, required the development of a novel egg phospholipid formulation, which is unpopular with patients and clinicians. Having accepted HSP90 or any other molecular target as a viable lead for drug discovery, how does one find sufficient molecules to test against this target, particularly if an initial lead looks like it may...

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...