“Druglike” character for a molecule entails a molecular weight of 350–400, if possible, and sufficient water solubility to be dispersed in aqueous media with concomitant lipophilic property to dissolve into and diffuse through lipid bilayer membranes. Show In vitro assays can be used to measure the ability of a molecule to diffuse through lipid membranes (PAMPA) and biological layers of cells (i.e., Caco-2, MDCK). •Assistance in absorption and or selectivity can be achieved by judicious choice of drug route of entry. •The two main independent parameters in pharmacokinetics are drug clearance and volume of distribution; from these, the third important parameter of half-life can be determined. •Clearance is mainly hepatic or renal; hepatic clearance is quantified by treating the liver as a virtual enzyme. Renal clearance is determined by glomerular filtration, active secretion, and reabsorption. •The volume of distribution of a drug can be used to determine where it is sequestered in the body. •Drug half-life can be used to determine dosing schedule and the time to attain a steady-state equilibrium concentration. •Bioavailability involves the interplay of absorption and the first-pass effect, whereby an orally absorbed drug must first pass through the liver before it enters the central compartment. •Nonlinear pharmacokinetics occur when elimination processes are saturated or the normally linear relationship between dosing and plasma concentration is exceeded either in capacity or sensitivity. •Clearance, volume of distribution, and t1/2 can be determined from a single i.v. dose experiment; addition of an oral dosing yields F. •Multiple dosing experiments can quickly detect nonlinear pharmacokinetics and enzyme induction. View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780128139578000096 PharmacokineticsMark Kester PhD, ... Kent E. Vrana PhD, in Elsevier's Integrated Review Pharmacology (Second Edition), 2012 Top five list1. Pharmacokinetics comprise a collection of equations that predict drug concentrations at the target site over time. 2.Pharmacokinetic principles integrate drug absorption, distribution, metabolism, and excretion (ADME). 3.Practitioners often need to know mathematical terms specific for a drug (t½, bioavailability) as well as for a patient (volume of distribution, clearance) to determine the steady-state concentration of drug in plasma (Cpss). 4.Because clearance and volume of distribution change in patients as a function of disease or age, practitioners often need to quantify plasma concentrations of drug directly (from laboratory measurements) to ensure that drugs reach therapeutically effective concentrations without causing toxic effects. 5.Frequently, practitioners must determine volume of distribution and clearance in selected groups of patients (i.e., in renal, gastrointestinal, or hepatic disease). This is necessary to achieve appropriate therapeutic responses. Self-assessment questions can be accessed atwww.StudentConsult.com. View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B978032307445200001X PharmacokineticsWayne L. Backes, in xPharm: The Comprehensive Pharmacology Reference, 2007 Most drugs exert their pharmacologic effects by binding to macromolecules known as receptors. Therefore, for a drug to produce a pharmacologic effect, it must be structurally capable of interacting with the appropriate receptor. However, the ability of a drug to interact with the receptor is not the only characteristic required for a therapeutically useful agent because it also must be capable of accumulating in the vicinity of the receptor site at a sufficient concentration. Pharmacokinetics is the aspect of pharmacology dealing with how drugs reach their site of actionand are removed from the body. The following processes govern the rate of accumulation and removal of drug from an organism–absorption, distribution, metabolism, and excretion. Details of pharmacokinetics are provided in the following sites in this work: 1.Drug transport across membranes–For a drug to transfer to its site of action, mechanisms must be available to allow the drug to traverse numerous biological membranes. These include passive diffusion, filtration, active transport, and endocytosis. These mechanisms are also important for the transfer of endogenous substances required for life. 2.Drug administration–Drugs can enter the body from several sites, with the route of administration having a significant influence on the ability of a drug to accumulate at its site of action. 3.Drug absorption–Drugs can be absorbed into the circulation from numerous sites within the body. 4.Drug distribution–Once in the circulation, the drug is transferred to the interstitial fluid and to the cells of the body. 5.Drug biotransformation–There is an increased interest in the chemical changes in a drug once it enters the body. In most cases, these drug biotransformation reactions produce intermediates with less pharmacologic activity than the parent compound; however, some drug metabolites possess significant pharmacologic action. Furthermore, some metabolites are chemically reactive and capable of contributing to toxicity, mutagenesis, carcinogenesis, and birth defects. 6.Drug excretion–The primary sites for drug excretion are the liver and kidney, although the skin, lungs, and bile and intestine may be sites for excretion as well. 7.Clinical pharmacokinetics–Each of the above processes affect not only the rate of accumulation of a drug at its site action, but also its rate of removal. Clinical pharmacokinetics provides a quantitative description in humans of the behavior of drugs with different characteristics as well as the differences expected from different routes of drug administration. View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780080552323600650 PharmacokineticsStan K. Bardal BSc (Pharm), MBA, PhD, ... Douglas S. Martin PhD, in Applied Pharmacology, 2011 Basic ConceptsDrug TransferDrugs must traverse a number of barriers to be absorbed, distributed, and eliminated. Major mechanisms are described in the following paragraphs. Passive DiffusionPassive diffusion is proportional to the concentration gradient of drug between two adjacent compartments, the thickness of the barrier, and the drug's ability to dissolve into the barrier separating the two compartments. These barriers are generally lipid membranes. Therefore the degree of ionization and the lipid solubility will affect passive drug transfer. Active TransportActive transport is mediated by a very large family of transporters collectively referred to as ATP binding cassette transporters (or ABC transporters). These transporters rely on adenosine triphosphate (ATP) as a source of energy to transport drug molecules across biologic membranes. There are several important features of this mechanism, including saturability, structural selectivity, and ATP dependence. In contrast to passive diffusion, these carriers often exhibit a concentration beyond which no further increase in transport occurs. These transporters exhibit a varying degree of structural selectivity for drugs and endogenous molecules. Structurally similar molecules will compete for binding at these transporters. This is an important mechanism of drug interaction. ▪ ATP dependence refers to the ability to move drugs against a concentration gradient. ▪Examples of the ATP binding cassette group of transporters include the multidrug resistance transporters (MDR transporters) such as P-glycoprotein (Pgp, MDR1 or ABCB1). ▴P-glycoprotein is an efflux transporter that transports drugs out of cell to the extracellular space. ▴P-glycoprotein is found in a number of locations, including the gut and the blood-brain barrier. ▴P-glycoprotein plays an important role in drug pharmacokinetics and in drug interactions. •In the intestine, P-glycoprotein substrates that diffuse into intestinal epithelial cells are pumped back into the intestinal lumen, reducing their absorption. P-glycoprotein is also found in the endothelial cells of the blood brain barrier. Substances that diffuse into these cells and are substrates for P-glycoprotein can be transported back out into the blood, limiting their penetration into the brain. •Drugs that inhibit P-glycoprotein increase the absorption of P-glycoprotein substrates. •Drugs or disease conditions that induce P-glycoprotein decrease absorption of P-glycoprotein substrates. Facilitated TransportFacilitated transport is mediated by another large family of transporters collectively referred to as the human solute-linked carrier (SLC) family. This group of transporters is similar to the ABC transporters with the exception that they do not directly bind and hydrolyze ATP as a source of energy. Examples of this type of transporter include the organic ion transporter in the renal tubules that is responsible for secretion of some diuretics into the renal tubule, their site of action. Drug PropertiesThe general chemical properties of a drug can greatly influence its pharmacokinetics. For a drug to be absorbed and distributed to its site of action or its site of elimination, it must be liberated from its formulation, it must dissolve in aqueous solutions, and at the same time it must be able to cross several hydrophobic barriers (e.g., plasma membrane). Drug Formulations (Table 2-1)▪ Solid formulations (e.g., tablets, capsules, suppositories) must disintegrate to release the drug. Disintegration of the dosage form may be compromised under certain conditions (e.g., dry mouth caused by aging, disease, or concurrent drug treatment slows dissolution of nitroglycerin tablets). On the other hand, drugs may be specifically formulated to allow disintegration only in certain sections of the gastrointestinal (GI) tract (e.g., enteric-coated tablets disintegrate in the small intestine), for the purpose of protecting the drug from destruction by gastric acid of the stomach (e.g., erythromycin) or protecting the stomach from an irritant drug (e.g., enteric-coated aspirin). Tablets and capsules may also be formulated to slowly release drugs (controlled-release, extended-release, or sustained-release formulations) and prolong their duration of action. Sustained-release formulations are particularly useful for drugs that have very short durations of action (see Table 2-1). ▪Semisolid formulations include creams, ointments, and pastes. These formulations are generally for topical application to the skin and require liberation and diffusion of the drug across the skin. ▪Liquid formulations may be suspensions or solutions, which do not require disintegration of the formulation and thus are generally absorbed more readily than solid formulations. Suspensions or solutions are also advantageous for patients who cannot swallow tablets or capsules. Drugs in suspension are not dissolved in the liquid vehicle. Therefore, the drug must first dissolve before it can be absorbed. Drugs in solution are already dissolved. Consequently, solutions are generally absorbed more rapidly than suspensions. Drug solutions may also be administered directly into the bloodstream. ▪Polymer formulations are a special category of solid formulations that incorporate the drug into a matrix that then gradually releases the drug over a prolonged period of time or at specific locations. Examples include transdermal patches and drug-eluting stents. Novel polymer-based formulations for intravenous (IV) delivery are also being designed. Drug ChemistryThe physical and chemical properties of a drug will influence its ability to traverse biologic membranes and to be dissolved and transported in biologic fluids. ▪Molecular size and shape. Smaller molecules are absorbed more readily. Drug shape affects affinity of the drug for carrier molecules or other binding sites such as plasma proteins or tissue. Drugs of similar structure may exhibit competition for such binding sites, which can affect their pharmacokinetics. ▪State of ionization. The nonionized form of drugs is more lipid permeable and therefore better able to diffuse across biologic barriers. The pKa is a characteristic of the drug and reflects the pH at which the drug will be equally partitioned between the ionized and nonionized forms. ▪The lipid-water partition coefficient is an index of lipid solubility. Drugs with higher lipid-water partition coefficients will cross biologic membranes more quickly. Effect of pHMost drugs are weak acids or bases and, as such, in solution show varying degrees of dissociation into their ionized and nonionized forms. The distribution between ionized and nonionized forms will be determined by the pKa of the drug and the pH of the solution in which the drug is dissolved. ▪For drugs that are weak acids, the following equation applies, where HA = drug with proton, which is therefore nonionized. H+ = proton, and A− is the ionized drug. HA⇌H++A− ▪Under basic conditions, weak acids are ionized to a greater extent (because the basic environment will shift the reaction to the right). ▪Under acidic conditions, weak acids are nonionized to a greater extent (because the acidic environment will shift the reaction to the left). ▪The greater the difference between the pH and the pKa, the greater the degree of ionization or nonionization. ▪The relationship between the pH of the drug's environment and the degree of its ionization is determined by the Henderson-Hasselbalch equation: Henderson-Hasselbalch Equation Applied to Acidic Drugs Log[HA][A−]=pKa−pH ▪For drugs that are weak bases, the reverse is true compared with weak acids: HB+ = drug with proton, which is therefore ionized. H+ = proton, and B is the nonionized drug. HB+⇌H++B ▪Under basic conditions, weak bases are nonionized to a greater extent (because the basic environment will shift the reaction to the right). ▪Under acidic conditions, weak bases are ionized to a greater extent (because the acidic environment will shift the reaction to the left). ▪Again, the greater the difference between the pH and the pKa, the greater the degree of ionization or nonionization. ▪The relationship between the pH of the drug's environment and the degree of its ionization is determined by the Henderson-Hasselbalch equation: Henderson-Hasselbalch Equation Applied to Basic Drugs Log[BH+][B]=pKa−pH The practical implications are as follows: The ionized form of the drug may become stranded in certain locations. This effect, referred to as ion trapping or pH trapping, occurs when drugs accumulate in a certain body compartment because they can diffuse into this area, but then become ionized owing to the prevailing pH and are unable to diffuse out of this location. An example, shown in Figure 2-1, is the trapping of basic drugs (e.g., morphine, pKa 7.9) in the stomach. The drug is approximately 50% nonionized in the plasma (pH approximately 7.4) because it is in an environment with a pH close to its pKa. In the stomach (pH approximately 2), the drug is highly ionized (approximately 200,000×), it cannot diffuse across the cells lining the stomach, and the drug molecules are trapped in the stomach. The concepts of acidic and basic drugs and their relative ionization at different pH values can be used clinically. For example, acidification of the urine is used to increase the elimination of amphetamine, a basic drug with pKa approximately 9.8. Rendering the urine acidic increases the amount of amphetamine in the ionized state, preventing its reabsorption from the urine into the bloodstream. Conversely, alkalinization of the urine is used to increase the excretion of acetylsalicylic acid (aspirin), an acidic drug. Increasing the pH of urine above the pKa of acetylsalicylic acid increases the proportion of the drug in the ionized state by about 10,000 times. The ionized form of the drug is not able to be reabsorbed across the renal tubule into the bloodstream. Moreover, the low concentration of the non-ionized form in the renal tubule compared with that in the blood favors diffusion of the non-ionized drug into the renal tubules (see Figure 2-2). View chapterPurchase book Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9781437703108000026 PharmacokineticsGeorge M. Kapalka, in Nutritional and Herbal Therapies for Children and Adolescents, 2010 Systemic CirculationBecause compounds in systemic circulation are delivered throughout the body, they are delivered to every body compartment and organ, not just to the desired target site. This is important to remember, since the same compound may exert different effects in various parts of the body. For example, even though a supplement is taken to change an aspect of brain function, that same supplement may exert undesirable effects in the GI tract (by changing gastric motility and causing diarrhea), in the heart (by affecting the heart rhythm), and in muscles that control movement (by causing tremors). Often the desired effects (change in brain function) may take some time, while other effects in the body may be more immediate. The balance between the two must always be carefully monitored. When a substance begins to be absorbed, it starts to enter systemic circulation. The rate of absorption can be measured, and is often indicated in reference literature. The time it takes for half of the compound generally available for distribution to reach systemic circulation is referred to as distribution half-life, and it reflects the rate and extent of absorption (this is different than the elimination half-life discussed later in the chapter). Sometimes referred to as terminal half-life, this is especially relevant in multiple dosing regimens, because it determines the concentration, fluctuation, and the time required to reach equilibrium (also discussed later in the chapter). As the compound enters systemic circulation, and assuming it is able to cross the blood–brain barrier (as reviewed below), the supplement may begin to exert the therapeutic effect. The more compound enters the blood stream the more clinical effect may be evident. However, as the compound enters systemic circulation, it also begins to be metabolized and excreted. Thus, what remains in circulation at any point in time is the result of the additive processes of absorption, and the subtractive processes of metabolism and excretion. The onset and strength of the therapeutic effect are determined by these pharmacokinetics, and generally speaking the onset of the effects (desired and adverse) will occur during the specified distribution half-life of the substance. Once this period elapses, unless additional doses are administered, additional effects are not likely. When a substance is administered, we are not only interested in the time it takes to produce the onset of any effect, but also in the time it takes for a compound to exhibit efficacy. Efficacy is usually defined as a clinical effect that sufficiently lowers target symptoms. The degree of this effect is not well established, and varies depending on the definition that particular researchers choose to impose. Often, a substance is considered to have sufficient efficacy when it is able to produce a statistically significant drop in symptoms. This may only reduce symptoms by 50 percent, and often less. Clearly, the reader can note that all symptoms will not be eliminated, and another 50 percent (or more) of the symptoms remain. For this reason, a therapeutic response, as defined by research studies, may be very different than a therapeutic response that is sought during treatment. The onset of therapeutic effect, and efficacy, need to be differentiated from the maximum effect that can be sought with the use of the compound. The maximum effect is generally defined as the maximum reduction in symptoms that can be attained with the use of the substance. Usually the maximum effect is established as the maximum dose above which further improvement in symptoms is not likely or may produce side effects that make further use impractical. Medications often have maximum dose limits established from prior research, and such limits for some supplements have also been established, although the majority of nutritional and herbal compounds have not undergone such careful research, so the maximum dose may need to be determined on a case-by-case basis by monitoring response and adverse effects. Generally, the dose above which improvement in symptoms is not evident and/or the side effects become difficult to manage needs to be regarded as the maximum therapeutic dose for the patient in question. Potency is the strength of the compound in exerting its effect. Although the ‘effect’ usually refers to the desired changes in target symptoms, adverse effects are also related, since many substances exhibit dose-related increases in both, desired and adverse effects. Potent supplements require low doses to produce an effect, and compounds with low potency require much higher doses. However, potency in and of itself usually has little effect on efficacy. Even though less potent compounds require much higher doses, this does not necessarily mean that higher doses will also result in more adverse effects. Usually, the potency of a substance is only important in determining the strength of the dose that must be administered. Varying potency is the factor that determines that one substance may be effective at 10 mg, while another may require 100 or 1000 mg before efficacy is evident. Toxicity is the level at which a substance becomes dangerous to the system. It is sometimes related to potency, in that substances that exhibit stronger binding affinities may also be more likely to cause toxic effects. However, in some cases less potent supplements are more likely to become toxic, since more of the compound needs to be taken to exert clinical effect, and dose-response curves may be different for desired effects and side effects (meaning that side effects become evident before clinical effects begin). Although doses or plasma levels that are likely to result in toxicity are sometimes established, adverse effects always must be carefully monitored in order to watch for signs of toxicity. As an example, St. John’s Wort is a compound with low potency that must be taken at high doses (usually, above 1000 mg/day) in order to be effective. However, toxicity becomes more likely with high doses, and may be signaled by tremors, agitation, and other symptoms of so-called ‘serotonin syndrome.’ When a patient takes this compound it is necessary to carefully monitor both desired and adverse effects to maximize therapeutic gains, and a dose must be sought that simultaneously maximizes clinical effects while avoiding serious side effects and toxicity. |
