pharma deel sensory science - Nutrition and Pharmacology some background on PK 1 Pharmacology and - Studeersnel (2025)

Studiejaar: 2024/2025

Preview tekst

Nutrition and Pharmacology some background on PK 1 Pharmacology and drug action Introduction In order to help keeping the overview and better understand the other paragraphs, some general principles on drug fate and action and terms will be explained first. Most of it will come back later during the course. As mentioned earlier, Pharmacology can be defined as the science that deals with intentional interactions between substances and living organisms in order to produce a positive change in function (Or : the study of the effects of drugs on the function of living systems). Pharmacology partly overlaps with toxicology. Toxicology is basically the study of the adverse effects of chemicals on living organisms. However, what is adverse, what is therapeutic? Sometimes it is not easy to make the difference. According to Paracelsus: dosis facit (only dose makes the poison). Pharmacology is often divided into two main sub disciplines: Pharmacodynamics and Pharmacokinetics. We will essentially follow this same division. Pharmacodynamics, sometimes described as what a drug does to the body, involves the molecular interaction of a compound with its target(s). This target can be an enzyme, a receptor, another macromolecule etc. Selectivity is often relative and many compounds interact with more than one target. Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, and out of the body, the time course of its absorption, bioavailability, distribution, metabolism, and excretion. Drug pharmacokinetics determines the onset, duration, and intensity of a effect. In addition to the above, some other terms are in use which sometimes leads to some confusion: Pharmacy Pharmaceutical sciences refers to the science and practice of formulating active substances to medicinal products (formulations). In the vast majority of cases, one or more technical ingredients (excipients, NL: hulpstoffen) are necessary to get the actives into the patient and to the of action. Pharmacotherapy deals with the actual treatment of patients with drugs. 1 Nutrition and Pharmacology some background on PK 1 Pharmacology and drug action Introduction In order to help keeping the overview and better understand the other paragraphs, some general principles on drug fate and action and terms will be explained first. Most of it will come back later during the course. As mentioned earlier, Pharmacology can be defined as the science that deals with intentional interactions between substances and living organisms in order to produce a positive change in function (Or : the study of the effects of drugs on the function of living systems). Pharmacology partly overlaps with toxicology. Toxicology is basically the study of the adverse effects of chemicals on living organisms. However, what is adverse, what is therapeutic? Sometimes it is not easy to make the difference. According to Paracelsus: dosis facit (only dose makes the poison). Pharmacology is often divided into two main sub disciplines: Pharmacodynamics and Pharmacokinetics. We will essentially follow this same division. Pharmacodynamics, sometimes described as what a drug does to the body, involves the molecular interaction of a compound with its target(s). This target can be an enzyme, a receptor, another macromolecule etc. Selectivity is often relative and many compounds interact with more than one target. Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, and out of the body, the time course of its absorption, bioavailability, distribution, metabolism, and excretion. Drug pharmacokinetics determines the onset, duration, and intensity of a effect. In addition to the above, some other terms are in use which sometimes leads to some confusion: Pharmacy Pharmaceutical sciences refers to the science and practice of formulating active substances to medicinal products (formulations). In the vast majority of cases, one or more technical ingredients (excipients, NL: hulpstoffen) are necessary to get the actives into the patient and to the of action. Pharmacotherapy deals with the actual treatment of patients with drugs. 1 Nutrition and Pharmacology some background on PK 2 PK introduction and some definitions Pharmacokinetics (PK) describes the time course of Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs in the body. For reasons of simplicity, we will use the general term pharmacokinetics. Pharmacokinetics is a term used pharmacologists. However, it should be realised that almost everything discussed here goes far beyond the behaviour of compounds that happen to be used as drugs. Toxicologists sometimes use the term toxicokinetics, others use biokinetics and perhaps one might come across the term nutrikinetics. 2 What can be done with pharmacokinetics ? There are a number of reasons to use PK : 1. To help understanding the relation between dose and effects and their time relation It has been observed that after the administration of a drug, the concentration of the drug in the body can often be described rather simple exponential equations. Even though the processes, which the drug is absorbed, distributed, metabolized and excreted may be very complex, the kinetics can be simulated using relatively simple models. Using these models, we are often able to calculate concentrations at the site of action. Together with the knowledge of the pharmacodynamic properties, in particular the relation between concentration and effect, it is often possible to relate a dose to an effect. However, please keep in mind that not every compound follows this concept. The basic pharmacokinetic equations and models are based on blood (or plasma, serum etc) concentrations. As the pharmacological targets are usually located outside the blood circulation, the relation between plasma concentration and effect may also be determined other processes and steps. The same applies to the relationship. Some compounds (for example many drugs, in particular those of the older generations) work according to a and principle. 2 Nutrition and Pharmacology some background on PK 2 PK introduction and some definitions Pharmacokinetics (PK) describes the time course of Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs in the body. For reasons of simplicity, we will use the general term pharmacokinetics. Pharmacokinetics is a term used pharmacologists. However, it should be realised that almost everything discussed here goes far beyond the behaviour of compounds that happen to be used as drugs. Toxicologists sometimes use the term toxicokinetics, others use biokinetics and perhaps one might come across the term nutrikinetics. 2 What can be done with pharmacokinetics ? There are a number of reasons to use PK : 1. To help understanding the relation between dose and effects and their time relation It has been observed that after the administration of a drug, the concentration of the drug in the body can often be described rather simple exponential equations. Even though the processes, which the drug is absorbed, distributed, metabolized and excreted may be very complex, the kinetics can be simulated using relatively simple models. Using these models, we are often able to calculate concentrations at the site of action. Together with the knowledge of the pharmacodynamic properties, in particular the relation between concentration and effect, it is often possible to relate a dose to an effect. However, please keep in mind that not every compound follows this concept. The basic pharmacokinetic equations and models are based on blood (or plasma, serum etc) concentrations. As the pharmacological targets are usually located outside the blood circulation, the relation between plasma concentration and effect may also be determined other processes and steps. The same applies to the relationship. Some compounds (for example many drugs, in particular those of the older generations) work according to a and principle. 2 Nutrition and Pharmacology some background on PK Intranasal eye oral lung ear sublingual i. i. LIVER S. BLOOD local rectal vaginal Figure Possible routes of administering a compound to the body. Drug in dosage form dissolution Drug in solution at absorption site absorption Drug in plasma (free and bound to proteins) Site of Tissues action biotransformation excretion (free bound) figure Schematic overview of the fate of a compound in the body. 4 Nutrition and Pharmacology some background on PK Intranasal eye oral lung ear sublingual i. i. LIVER S. BLOOD local rectal vaginal Figure Possible routes of administering a compound to the body. Drug in dosage form dissolution Drug in solution at absorption site absorption Drug in plasma (free and bound to proteins) Site of Tissues action biotransformation excretion (free bound) figure Schematic overview of the fate of a compound in the body. 4 Nutrition and Pharmacology some background on PK 3 Basic ADME terms and processes 3 Absorption Drug absorption is determined the physicochemical properties, formulation, and route of administration. Dosage forms (e. tablets, capsules, solutions), consisting of the drug plus other ingredients, are formulated to be given various routes (e. oral, buccal, sublingual, rectal, parenteral, topical, inhalational). Drugs must be in solution to be absorbed. Thus, solid forms (e. tablets) must be able to disintegrate and disaggregate. Unless given i., a drug must cross several semi permeable cell membranes before it reaches the systemic circulation. Cell membranes are biologic barriers that selectively inhibit passage of drug molecules. The membranes are composed primarily of a bimolecular lipid matrix, which determines membrane permeability characteristics. Figure summarizes the possible transport routes of a compound through the intestinal epithelium. Drugs may cross cell membranes passive diffusion, A Paracellular B Transcellular (passive) C Transcellular (active uptake) D Transcellular (active extrusion) E Sequestration in vesicles apical A B C D E B 7 B D A B C D E basal Figure Schematic overview of transport routes from the GI tract to the blood. facilitated passive diffusion, active transport, or pinocytosis. Sometimes various globular proteins embedded in the matrix function as receptors and help transport molecules across the membrane. 5 Nutrition and Pharmacology some background on PK 3 Basic ADME terms and processes 3 Absorption Drug absorption is determined the physicochemical properties, formulation, and route of administration. Dosage forms (e. tablets, capsules, solutions), consisting of the drug plus other ingredients, are formulated to be given various routes (e. oral, buccal, sublingual, rectal, parenteral, topical, inhalational). Drugs must be in solution to be absorbed. Thus, solid forms (e. tablets) must be able to disintegrate and disaggregate. Unless given i., a drug must cross several semi permeable cell membranes before it reaches the systemic circulation. Cell membranes are biologic barriers that selectively inhibit passage of drug molecules. The membranes are composed primarily of a bimolecular lipid matrix, which determines membrane permeability characteristics. Figure summarizes the possible transport routes of a compound through the intestinal epithelium. Drugs may cross cell membranes passive diffusion, A Paracellular B Transcellular (passive) C Transcellular (active uptake) D Transcellular (active extrusion) E Sequestration in vesicles apical A B C D E B 7 B D A B C D E basal Figure Schematic overview of transport routes from the GI tract to the blood. facilitated passive diffusion, active transport, or pinocytosis. Sometimes various globular proteins embedded in the matrix function as receptors and help transport molecules across the membrane. 5 Nutrition and Pharmacology some background on PK stability, and patient acceptance. Because solid drug forms must dissolve before absorption can occur, the dissolution rate determines availability of the drug for absorption, and may become the step if slower than absorption. Manipulating the formulation (e. the form as salt, crystal, or hydrate) can change the dissolution rate and thus control overall absorption (Figure 3 Distribution After entering the systemic circulation, most compounds are distributed to the tissues. The extent of distribution and the tissues where the drug is penetrating are highly dependent on the chemical properties of the molecule. Distribution is generally uneven because of differences in blood perfusion, tissue binding (e. because of lipid content), regional pH, and permeability of cell membranes. The entry rate of a drug into a tissue also depends on the rate of blood flow to the tissue, tissue mass, and partition characteristics between blood and tissue. For interstitial fluids of most tissues, the drug distribution rate is determined primarily perfusion. For poorly perfused tissues (e. muscle, fat), distribution is very slow, especially if the tissue has a high affinity for the drug. A distribution equilibrium (when entry and exit rates are the same) between blood and tissue is reached more rapidly in richly vascularised areas, unless diffusion across cell membranes is the step. After equilibrium, drug concentrations in tissues and in extracellular fluids are reflected the plasma concentration. This means that the ratios are more or less constant. However, it certainly does not mean that the concentration of the compound throughout the body is equal! Metabolism and excretion occur simultaneously with distribution, making the process dynamic and complex. The principles of drug distribution will be discussed further in this handout, together with the term of Drugs reach the central nervous system (CNS) via brain capillaries and the cerebrospinal fluid (CSF). Although the brain receives about of the cardiac output, distribution of drugs to brain tissue is restricted because the permeability characteristics differ from those of other tissues barrier). Although some drugs (e. thiopental) enter the brain readily, polar compounds do not. The reason is the barrier, which consists of the endothelium of brain capillaries and the astrocytic sheath. The endothelial cells of brain capillaries hamper diffusion of drugs. This is because brain endothelial cells are more tightly joined to one another than those of most capillaries. With aging, the barrier may become less effective, allowing increased passage of compounds into the brain. Drugs may enter ventricular CSF directly via the choroid plexus, and then passively diffuse into brain tissue from CSF. Also in the choroid plexus, organic acids (e. penicillin) are actively transported from CSF to blood. 7 Nutrition and Pharmacology some background on PK stability, and patient acceptance. Because solid drug forms must dissolve before absorption can occur, the dissolution rate determines availability of the drug for absorption, and may become the step if slower than absorption. Manipulating the formulation (e. the form as salt, crystal, or hydrate) can change the dissolution rate and thus control overall absorption (Figure 3 Distribution After entering the systemic circulation, most compounds are distributed to the tissues. The extent of distribution and the tissues where the drug is penetrating are highly dependent on the chemical properties of the molecule. Distribution is generally uneven because of differences in blood perfusion, tissue binding (e. because of lipid content), regional pH, and permeability of cell membranes. The entry rate of a drug into a tissue also depends on the rate of blood flow to the tissue, tissue mass, and partition characteristics between blood and tissue. For interstitial fluids of most tissues, the drug distribution rate is determined primarily perfusion. For poorly perfused tissues (e. muscle, fat), distribution is very slow, especially if the tissue has a high affinity for the drug. A distribution equilibrium (when entry and exit rates are the same) between blood and tissue is reached more rapidly in richly vascularised areas, unless diffusion across cell membranes is the step. After equilibrium, drug concentrations in tissues and in extracellular fluids are reflected the plasma concentration. This means that the ratios are more or less constant. However, it certainly does not mean that the concentration of the compound throughout the body is equal! Metabolism and excretion occur simultaneously with distribution, making the process dynamic and complex. The principles of drug distribution will be discussed further in this handout, together with the term of Drugs reach the central nervous system (CNS) via brain capillaries and the cerebrospinal fluid (CSF). Although the brain receives about of the cardiac output, distribution of drugs to brain tissue is restricted because the permeability characteristics differ from those of other tissues barrier). Although some drugs (e. thiopental) enter the brain readily, polar compounds do not. The reason is the barrier, which consists of the endothelium of brain capillaries and the astrocytic sheath. The endothelial cells of brain capillaries hamper diffusion of drugs. This is because brain endothelial cells are more tightly joined to one another than those of most capillaries. With aging, the barrier may become less effective, allowing increased passage of compounds into the brain. Drugs may enter ventricular CSF directly via the choroid plexus, and then passively diffuse into brain tissue from CSF. Also in the choroid plexus, organic acids (e. penicillin) are actively transported from CSF to blood. 7 Nutrition and Pharmacology some background on PK 3 Excretion The kidneys, which excrete substances, are the principal organs of excretion. Generally, the contribution of intestine, saliva, sweat, breast milk, and lungs to excretion is small, except for exhalation of volatile anaesthetics. Excretion via breast milk, although not important to the mother, may affect the breastfeeding infant. Hepatic metabolism often makes drugs more polar and thus more water soluble. The resulting metabolites are then more readily excreted.. Excretion via the bile occurs. However, part of it can be which is called the entero hepatic cycle. Renal filtration accounts for most drug excretion. About of the plasma reaching the glomerulus is filtered through pores in the glomerular nearly all water and most electrolytes are passively and actively reabsorbed from the renal tubules back into the circulation. However, polar compounds, which include most drug metabolites, cannot diffuse back into the circulation and are excreted unless a specific transport mechanism exists for their reabsorption (eg, as for glucose, ascorbic acid, and B vitamins). With aging, renal drug excretion decreases, and at the age of 80, renal clearance is typically reduced to of what it was at an age of 30. Drugs bound to plasma proteins remain in the only unbound drug is contained in the glomerular filtrate. forms of drugs and their metabolites tend to be reabsorbed readily from tubular fluids. Urinary pH, which varies from 4 to 8, may affect drug reabsorption and excretion determining whether a weak acid or base is in an or ionized form. Acidification of urine increases reabsorption and decreases excretion of weak acids and decreases reabsorption of weak bases. Alkalinisation of urine has the opposite effect. In some cases of overdose, these principles are used to enhance the excretion of weak bases or eg, urine is alkalinized to enhance excretion of acetylsalicylic acid. The opposite is sometimes practised in sports doping or illegal use of compounds in animals. The purpose of this is to lower the concentration of a compound in urine to mislead control procedures. Diet has an effect on urinary pH. However there seem to be hardly any data that support the idea that this may lead to a interaction in practice. Active tubular secretion in the proximal tubule is important in the elimination of many drugs. This process may be blocked metabolic inhibitors. When a drug concentration is high, secretory transport can reach an upper limit (transport each substance has a characteristic transport maximum. Anions and cations are handled separate transport mechanisms. Normally, the anion secretory system eliminates metabolites conjugated with glycine, sulphate, or glucuronic acid. Anions (weak acids) compete with each other for secretion. This competition can be used eg, probenecid blocks the normally rapid tubular secretion of penicillin, resulting in higher plasma penicillin concentrations for a longer time. In the cation transport system, cations or 8 Nutrition and Pharmacology some background on PK 3 Excretion The kidneys, which excrete substances, are the principal organs of excretion. Generally, the contribution of intestine, saliva, sweat, breast milk, and lungs to excretion is small, except for exhalation of volatile anaesthetics. Excretion via breast milk, although not important to the mother, may affect the breastfeeding infant. Hepatic metabolism often makes drugs more polar and thus more water soluble. The resulting metabolites are then more readily excreted.. Excretion via the bile occurs. However, part of it can be which is called the entero hepatic cycle. Renal filtration accounts for most drug excretion. About of the plasma reaching the glomerulus is filtered through pores in the glomerular nearly all water and most electrolytes are passively and actively reabsorbed from the renal tubules back into the circulation. However, polar compounds, which include most drug metabolites, cannot diffuse back into the circulation and are excreted unless a specific transport mechanism exists for their reabsorption (eg, as for glucose, ascorbic acid, and B vitamins). With aging, renal drug excretion decreases, and at the age of 80, renal clearance is typically reduced to of what it was at an age of 30. Drugs bound to plasma proteins remain in the only unbound drug is contained in the glomerular filtrate. forms of drugs and their metabolites tend to be reabsorbed readily from tubular fluids. Urinary pH, which varies from 4 to 8, may affect drug reabsorption and excretion determining whether a weak acid or base is in an or ionized form. Acidification of urine increases reabsorption and decreases excretion of weak acids and decreases reabsorption of weak bases. Alkalinisation of urine has the opposite effect. In some cases of overdose, these principles are used to enhance the excretion of weak bases or eg, urine is alkalinized to enhance excretion of acetylsalicylic acid. The opposite is sometimes practised in sports doping or illegal use of compounds in animals. The purpose of this is to lower the concentration of a compound in urine to mislead control procedures. Diet has an effect on urinary pH. However there seem to be hardly any data that support the idea that this may lead to a interaction in practice. Active tubular secretion in the proximal tubule is important in the elimination of many drugs. This process may be blocked metabolic inhibitors. When a drug concentration is high, secretory transport can reach an upper limit (transport each substance has a characteristic transport maximum. Anions and cations are handled separate transport mechanisms. Normally, the anion secretory system eliminates metabolites conjugated with glycine, sulphate, or glucuronic acid. Anions (weak acids) compete with each other for secretion. This competition can be used eg, probenecid blocks the normally rapid tubular secretion of penicillin, resulting in higher plasma penicillin concentrations for a longer time. In the cation transport system, cations or 8 Nutrition and Pharmacology some background on PK 3.4 Cytochrome P450 Cytochrome P450 (CYP450) is an enzyme complex that catalyses many reactions. CYP450 is called a of enzymes with (different members present in all living organisms. In humans, more than 50 enzymes have been identified to date. CYP450 enzymes catalyse many reactions of both endogenous compounds as well as foreign molecules. CYP450 (Fe ) CYP450 reductase drug (RH) complex drug (R) reduced flavoprotein et NADPH oxidized CYP450 (Fe flavoprotein CYP450 oxidized CYP450 drug RH CYP450 ROH H2O O2 et RH CYP450 O2 Figure Reaction scheme of a typical CYP450 enzyme complex. CYP450 is for example vital to the formation of cholesterol, steroids and arachidonic acid metabolites. In addition to these endogenous molecules, CYP450 enzymes are the most important enzymes that catalyse the oxidation of many drugs and other molecules (plant metabolites, environmental contaminants etc.) we are exposed to. Although the process is called oxidation, the reactions that are seen also include hydroxylations as well as epoxidations and oxidations. The electrons necessary for the oxidation are supplied NADPH (cytochrome reductase, a flavoprotein that transfers electrons from NADPH (the reduced form of nicotinamideadenine dinucleotide phosphate) to cytochrome The reaction scheme is depicted in Figure For drugs, the CYP450 families are the most involved in biotransformation. The families are further divided into subfamilies that contain individual enzymes. The individual enzymes show substrate 10 Nutrition and Pharmacology some background on PK 3.4 Cytochrome P450 Cytochrome P450 (CYP450) is an enzyme complex that catalyses many reactions. CYP450 is called a of enzymes with (different members present in all living organisms. In humans, more than 50 enzymes have been identified to date. CYP450 enzymes catalyse many reactions of both endogenous compounds as well as foreign molecules. CYP450 (Fe ) CYP450 reductase drug (RH) complex drug (R) reduced flavoprotein et NADPH oxidized CYP450 (Fe flavoprotein CYP450 oxidized CYP450 drug RH CYP450 ROH H2O O2 et RH CYP450 O2 Figure Reaction scheme of a typical CYP450 enzyme complex. CYP450 is for example vital to the formation of cholesterol, steroids and arachidonic acid metabolites. In addition to these endogenous molecules, CYP450 enzymes are the most important enzymes that catalyse the oxidation of many drugs and other molecules (plant metabolites, environmental contaminants etc.) we are exposed to. Although the process is called oxidation, the reactions that are seen also include hydroxylations as well as epoxidations and oxidations. The electrons necessary for the oxidation are supplied NADPH (cytochrome reductase, a flavoprotein that transfers electrons from NADPH (the reduced form of nicotinamideadenine dinucleotide phosphate) to cytochrome The reaction scheme is depicted in Figure For drugs, the CYP450 families are the most involved in biotransformation. The families are further divided into subfamilies that contain individual enzymes. The individual enzymes show substrate 10 Nutrition and Pharmacology some background on PK specificity to a certain degree. This means that the main biotransformation reactions of specific drugs are preferably catalysed this enzyme. An example is given in Table Table Separate CYP 450 enzymes show preference for specific substrates, in this case drugs. subfamilly enzymes Examples of substrates CYP1A caffeine, fenacetine, haloperidol, CYP2B carbamazepine, taxol CYP2C diclofenac, fenytoïne, tolbutamide, omeprazol, propranolol CYP2D debrisoquine, imipramine, bufurolol CYP2E alcoholen, div volatile anaesthetics CYP3A ethinyloestradiol, erythromycin, lidocaine, nifedipine, carbamazepine . many others ! This substrate preference is relevant for a number of reasons: Drug metabolism rates vary among patients. Part of this can be explained genetic polymorphism. This may lead to or metabolizers. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not in others, metabolism may be so slow that usual doses have toxic effects. Cytochrome enzymes can be induced or inhibited other drugs and dietary components CYP450 is affected many other factors such as disease, age, gender etc. For example, with aging, the capacity for metabolism through the cytochrome enzyme system is reduced because liver volume and hepatic flow are decreased. Because neonates have partially developed liver microsomal enzyme systems, they also have difficulty metabolizing many drugs. In many cases, only specific enzymes are affected or different. As a consequence, it depends on the biotransformation route of that drug whether or not this is therapeutically relevant. In terms of the relative amounts and number of drugs that are being metabolized, the enzymes CYP3A4, CYP2D6 and CYP2C19 appear to be the most important ones in human medicine. It is not surprising that much of the CYP450 in man is found in the liver, the main organ involved in drug metabolism, but a remarkable amount is also found in the small intestine. CYP usually sits around in the part of the cytoplasm (endoplasmic reticulum). 11 Nutrition and Pharmacology some background on PK specificity to a certain degree. This means that the main biotransformation reactions of specific drugs are preferably catalysed this enzyme. An example is given in Table Table Separate CYP 450 enzymes show preference for specific substrates, in this case drugs. subfamilly enzymes Examples of substrates CYP1A caffeine, fenacetine, haloperidol, CYP2B carbamazepine, taxol CYP2C diclofenac, fenytoïne, tolbutamide, omeprazol, propranolol CYP2D debrisoquine, imipramine, bufurolol CYP2E alcoholen, div volatile anaesthetics CYP3A ethinyloestradiol, erythromycin, lidocaine, nifedipine, carbamazepine . many others ! This substrate preference is relevant for a number of reasons: Drug metabolism rates vary among patients. Part of this can be explained genetic polymorphism. This may lead to or metabolizers. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not in others, metabolism may be so slow that usual doses have toxic effects. Cytochrome enzymes can be induced or inhibited other drugs and dietary components CYP450 is affected many other factors such as disease, age, gender etc. For example, with aging, the capacity for metabolism through the cytochrome enzyme system is reduced because liver volume and hepatic flow are decreased. Because neonates have partially developed liver microsomal enzyme systems, they also have difficulty metabolizing many drugs. In many cases, only specific enzymes are affected or different. As a consequence, it depends on the biotransformation route of that drug whether or not this is therapeutically relevant. In terms of the relative amounts and number of drugs that are being metabolized, the enzymes CYP3A4, CYP2D6 and CYP2C19 appear to be the most important ones in human medicine. It is not surprising that much of the CYP450 in man is found in the liver, the main organ involved in drug metabolism, but a remarkable amount is also found in the small intestine. CYP usually sits around in the part of the cytoplasm (endoplasmic reticulum). 11 Nutrition and Pharmacology some background on PK Suppose a drug is given as i. bolus and the plasma concentrations are measured. The graph depicted in Figure is obtained. When the (concentration) of the graph of Figure is changed to a logarithmic scale, we see that there is a linear relation between time and log concentration (Figure This behaviour can be expressed mathematically as: (5) Kel: the elimination constant (time ¹ Ct: the at an indefinite time point. When equation (5) is differentiated to t, we get equation (6): dC (6) The drug concentration is now directly proportional to the drug concentration at any time point. This is called elimination. If we double the dose, the concentration will double at each time point. In fact, most elimination processes appear to obey this elimination model. Elimination Rate Constant, kel The elimination rate constant (abbreviated as Kel, K10, and sometimes ke) is the first order rate constant describing drug elimination from the body. This is an overall elimination rate constant describing removal of the drug all elimination processes including excretion and metabolism. Metabolites are different chemical entities and have their own elimination rate constant. The elimination rate constant is the proportionality constant relating the rate of change in drug concentration and concentration OR the rate of elimination of the drug and the amount of drug remaining to be eliminated. of Elimination, Working with kel (with its reciprocal unit, time is usually not very practical. Most often we see the term elimination instead. Please note that is often used to define the concentration or just This may be confusing, especially because many reports are not consequent. The life is an empirical parameter and defined as the time taken for the plasma concentration to fall to half its original value. Units for this parameter are units of time such as hour, minute, or day. Thus Cp is the 13 Nutrition and Pharmacology some background on PK Suppose a drug is given as i. bolus and the plasma concentrations are measured. The graph depicted in Figure is obtained. When the (concentration) of the graph of Figure is changed to a logarithmic scale, we see that there is a linear relation between time and log concentration (Figure This behaviour can be expressed mathematically as: (5) Kel: the elimination constant (time ¹ Ct: the at an indefinite time point. When equation (5) is differentiated to t, we get equation (6): dC (6) The drug concentration is now directly proportional to the drug concentration at any time point. This is called elimination. If we double the dose, the concentration will double at each time point. In fact, most elimination processes appear to obey this elimination model. Elimination Rate Constant, kel The elimination rate constant (abbreviated as Kel, K10, and sometimes ke) is the first order rate constant describing drug elimination from the body. This is an overall elimination rate constant describing removal of the drug all elimination processes including excretion and metabolism. Metabolites are different chemical entities and have their own elimination rate constant. The elimination rate constant is the proportionality constant relating the rate of change in drug concentration and concentration OR the rate of elimination of the drug and the amount of drug remaining to be eliminated. of Elimination, Working with kel (with its reciprocal unit, time is usually not very practical. Most often we see the term elimination instead. Please note that is often used to define the concentration or just This may be confusing, especially because many reports are not consequent. The life is an empirical parameter and defined as the time taken for the plasma concentration to fall to half its original value. Units for this parameter are units of time such as hour, minute, or day. Thus Cp is the 13 Nutrition and Pharmacology some background on PK concentration at time one and is the concentration one later. Provided that it has been determined that the decline of the plasma concentration (the entire curve or the part of interest) is only caused pure elimination, one may use the term elimination In our example of Figure and Figure this is indeed the case. 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 time (hour) Figure model, first order elimination. 100 10 1 0 2 4 6 8 10 12 time (hour) Figure first order elimination with logarithmic Using the term in practice Following the definition, the is the time required to decrease the plasma concentration a factor 2. The is commonly used to establish dosing regimens (discussed further in this course). It is easy to calculate that after 5 over is lost or eliminated. Typically, with pharmacokinetic processes, this is considered the completion of the process (although in theory it takes 14 Nutrition and Pharmacology some background on PK concentration at time one and is the concentration one later. Provided that it has been determined that the decline of the plasma concentration (the entire curve or the part of interest) is only caused pure elimination, one may use the term elimination In our example of Figure and Figure this is indeed the case. 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 time (hour) Figure model, first order elimination. 100 10 1 0 2 4 6 8 10 12 time (hour) Figure first order elimination with logarithmic Using the term in practice Following the definition, the is the time required to decrease the plasma concentration a factor 2. The is commonly used to establish dosing regimens (discussed further in this course). It is easy to calculate that after 5 over is lost or eliminated. Typically, with pharmacokinetic processes, this is considered the completion of the process (although in theory it takes 14 Nutrition and Pharmacology some background on PK of distribution larger than the volume of the entire body (see examples in Error! Reference source not found.). The principle of Vd is also schematically depicted in Figure Dose C plasma plasma Figure Schematic representation of the principle of volume of distribution. A drug, given in a certain dose, distributes over different organs. The concentration of the drug is measured in plasma. The volume of distribution is definition the ratio between dose and Cplasma 4 Binding to or tissue proteins The extent of drug distribution into tissues depends on the extent of plasma protein and tissue binding. In the bloodstream, drugs are transported partly in solution as free (unbound) drug and partly reversibly bound to blood components (eg, plasma proteins, blood cells). Of the many plasma proteins that can interact with drugs, the most important are albumin, glycoprotein, and lipoproteins. Acidic drugs are usually bound more extensively to basic drugs are usually bound more extensively to acid glycoprotein, lipoproteins, or both. Only unbound drug is available for passive diffusion to extravascular or tissue sites where pharmacologic effects occur. Therefore, the unbound drug concentration in the systemic circulation typically determines drug the concentration at the active site and thus efficacy. At high drug concentrations, the amount of bound drug approaches an upper limit determined the number of available binding sites. Saturation of binding sites is the basis of displacement interactions among drugs. Drugs bind to many substances other than proteins. Binding usually occurs when a drug associates with a macromolecule in an aqueous environment but may occur when a drug is partitioned into body fat. Because fat is poorly perfused, equilibration time is long, especially if the drug 16 Nutrition and Pharmacology some background on PK of distribution larger than the volume of the entire body (see examples in Error! Reference source not found.). The principle of Vd is also schematically depicted in Figure Dose C plasma plasma Figure Schematic representation of the principle of volume of distribution. A drug, given in a certain dose, distributes over different organs. The concentration of the drug is measured in plasma. The volume of distribution is definition the ratio between dose and Cplasma 4 Binding to or tissue proteins The extent of drug distribution into tissues depends on the extent of plasma protein and tissue binding. In the bloodstream, drugs are transported partly in solution as free (unbound) drug and partly reversibly bound to blood components (eg, plasma proteins, blood cells). Of the many plasma proteins that can interact with drugs, the most important are albumin, glycoprotein, and lipoproteins. Acidic drugs are usually bound more extensively to basic drugs are usually bound more extensively to acid glycoprotein, lipoproteins, or both. Only unbound drug is available for passive diffusion to extravascular or tissue sites where pharmacologic effects occur. Therefore, the unbound drug concentration in the systemic circulation typically determines drug the concentration at the active site and thus efficacy. At high drug concentrations, the amount of bound drug approaches an upper limit determined the number of available binding sites. Saturation of binding sites is the basis of displacement interactions among drugs. Drugs bind to many substances other than proteins. Binding usually occurs when a drug associates with a macromolecule in an aqueous environment but may occur when a drug is partitioned into body fat. Because fat is poorly perfused, equilibration time is long, especially if the drug 16 Nutrition and Pharmacology some background on PK is highly lipophilic. Accumulation of drugs in tissues or body compartments can prolong drug action because the tissues release the accumulated drug as plasma drug concentration decreases. For example, thiopental is highly lipid soluble, rapidly enters the brain after a single i. injection, and has a marked and rapid anaesthetic the effect ends within a few minutes as the drug is redistributed to more slowly perfused fatty tissues. Thiopental is then slowly released from fat storage, maintaining anaesthetic plasma these levels may become significant if dosing of thiopental is repeated, causing large amounts to be stored in fat. Thus, storage in fat initially shortens the effect but then prolongs it. Some drugs accumulate within cells because they bind with proteins, phospholipids, or nucleic acids. For example, chloroquine concentrations in WBCs and liver cells can be thousands of times higher than those in plasma. A drug in cells is in equilibrium with that drug in plasma and moves into plasma as the drug is eliminated from the body. 4 Area under the curve (AUC) The area under the plasma (serum, or blood) concentration versus time curve (AUC) has a number of important applications in pharmacology and other life sciences. The AUC is a parameter and defined as follows: AUC (11) Please note that an AUC can only be determined or evaluated from a graph that has a linear (plasma concentration) scale. The AUC can be used as a measure of drug exposure. It is derived from a drug time curve so it gives a measure of the amount of drug and the a drug stays in a body. A long exposure to a low drug concentration may be as important as shorten exposure to a higher concentration. Some drugs are dosed using the AUC to quantitate the maximum tolerated exposure (AUC dosing). The AUC measured after administration of a drug product is an important parameter in the comparison of drug products. Studies can be performed where different drug products may be given to a panel of subject on separate equations. These bioequivalency or bioavailability studies can be analysed comparing AUC values (see further in the course). Drug AUC values can be used to determine other pharmacokinetic parameters, such as clearance and bioavailability (both explained further in the course). The area under the plasma concentration versus time curve (AUC) has units of concentration times time, for example, or 17 Nutrition and Pharmacology some background on PK is highly lipophilic. Accumulation of drugs in tissues or body compartments can prolong drug action because the tissues release the accumulated drug as plasma drug concentration decreases. For example, thiopental is highly lipid soluble, rapidly enters the brain after a single i. injection, and has a marked and rapid anaesthetic the effect ends within a few minutes as the drug is redistributed to more slowly perfused fatty tissues. Thiopental is then slowly released from fat storage, maintaining anaesthetic plasma these levels may become significant if dosing of thiopental is repeated, causing large amounts to be stored in fat. Thus, storage in fat initially shortens the effect but then prolongs it. Some drugs accumulate within cells because they bind with proteins, phospholipids, or nucleic acids. For example, chloroquine concentrations in WBCs and liver cells can be thousands of times higher than those in plasma. A drug in cells is in equilibrium with that drug in plasma and moves into plasma as the drug is eliminated from the body. 4 Area under the curve (AUC) The area under the plasma (serum, or blood) concentration versus time curve (AUC) has a number of important applications in pharmacology and other life sciences. The AUC is a parameter and defined as follows: AUC (11) Please note that an AUC can only be determined or evaluated from a graph that has a linear (plasma concentration) scale. The AUC can be used as a measure of drug exposure. It is derived from a drug time curve so it gives a measure of the amount of drug and the a drug stays in a body. A long exposure to a low drug concentration may be as important as shorten exposure to a higher concentration. Some drugs are dosed using the AUC to quantitate the maximum tolerated exposure (AUC dosing). The AUC measured after administration of a drug product is an important parameter in the comparison of drug products. Studies can be performed where different drug products may be given to a panel of subject on separate equations. These bioequivalency or bioavailability studies can be analysed comparing AUC values (see further in the course). Drug AUC values can be used to determine other pharmacokinetic parameters, such as clearance and bioavailability (both explained further in the course). The area under the plasma concentration versus time curve (AUC) has units of concentration times time, for example, or 17 Nutrition and Pharmacology some background on PK determination of suitable drug dosage regimens. The problem with the concept of clearance is that it is again also a rather abstract parameter in terms of physiological understanding. Clearance is often defined as plasma volume which is totally cleared of drug per unit of This is actually not something that is happening in real life. The dimension of clearance is (for example for the entire organism, or volume (kg bodyweight)¹. Mathematically, CI can be viewed as the proportionality constant relating the rate of the total elimination and the drug concentration (14): (14) In this equation (amount per time) is the rate of drug elimination at a given time t. The clearance of a drug is depends on: The extraction ratios of the organs that are involved in the elimination of the drug from the blood The blood flow through the organ(s) involved in the elimination, but only in case of clearance drugs (explained during the course) The presence of drug binding protein (in case of drugs e. digoxin and penicillin) Clearance can be calculated from the dose D, f (see further in the course) and the AUC: (15) Only for a model the following equation can be used: (16) Please note that this is a The process of clearance is not dependent on the distribution volume (kel is also determined Vd). 19 Nutrition and Pharmacology some background on PK determination of suitable drug dosage regimens. The problem with the concept of clearance is that it is again also a rather abstract parameter in terms of physiological understanding. Clearance is often defined as plasma volume which is totally cleared of drug per unit of This is actually not something that is happening in real life. The dimension of clearance is (for example for the entire organism, or volume (kg bodyweight)¹. Mathematically, CI can be viewed as the proportionality constant relating the rate of the total elimination and the drug concentration (14): (14) In this equation (amount per time) is the rate of drug elimination at a given time t. The clearance of a drug is depends on: The extraction ratios of the organs that are involved in the elimination of the drug from the blood The blood flow through the organ(s) involved in the elimination, but only in case of clearance drugs (explained during the course) The presence of drug binding protein (in case of drugs e. digoxin and penicillin) Clearance can be calculated from the dose D, f (see further in the course) and the AUC: (15) Only for a model the following equation can be used: (16) Please note that this is a The process of clearance is not dependent on the distribution volume (kel is also determined Vd). 19 Nutrition and Pharmacology some background on PK 4 Administration routes other than i. The most practical and hence the most common route of drug administration is the oral route. When a drug is given this route, absorption processes are involved. We will discuss the example of oral administration here, but note that from a pharmacokinetic perspective similar principles apply for other routes (intramuscular injection, rectal administration). Before the actual absorption starts, other processes such as disintegration of the formulation, release and dissolution of the compounds etc. are playing a role. In most kinetic applications we see these separate processes, but only the resulting absorption phase. 4.7 Bioavailability When absorption processes are involved, another term that becomes relevant is the bioavailability. Bioavailability refers to the extent to and rate at which the active moiety (drug or metabolite) enters the systemic circulation, there accessing the site of action. Bioavailability of a drug is determined the properties of the dosage form and the physicochemical properties of the drug. Differences in bioavailability among formulations of a given drug can have clinical thus, knowing whether drug formulations are equivalent is essential. Bioavailability can be calculated from: f AUC (21) The AUC obtained after i. administration serves as reference and the is used when AUCs are compared that have been obtained after different doses. There are a number of potential causes for low bioavailability. Orally administered drugs must pass through the intestinal wall and then through the portal circulation to the both are common sites of metabolism (metabolism of a drug before it reaches systemic circulation). Many drugs may be metabolized before adequate plasma concentrations are reached. Low bioavailability is most common with oral dosage forms of poorly soluble, slowly absorbed drugs. Insufficient absorption time in the GI tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (eg, if it is highly ionized and polar), the time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Age, sex, physical activity, genetic phenotype, stress, disorders (eg, achlorhydria, malabsorption syndromes), or previous GI surgery can also affect drug bioavailability. A term which is related but different from is Formulations are considered in extent and rate of absorption if their plasma 20 Nutrition and Pharmacology some background on PK 4 Administration routes other than i. The most practical and hence the most common route of drug administration is the oral route. When a drug is given this route, absorption processes are involved. We will discuss the example of oral administration here, but note that from a pharmacokinetic perspective similar principles apply for other routes (intramuscular injection, rectal administration). Before the actual absorption starts, other processes such as disintegration of the formulation, release and dissolution of the compounds etc. are playing a role. In most kinetic applications we see these separate processes, but only the resulting absorption phase. 4.7 Bioavailability When absorption processes are involved, another term that becomes relevant is the bioavailability. Bioavailability refers to the extent to and rate at which the active moiety (drug or metabolite) enters the systemic circulation, there accessing the site of action. Bioavailability of a drug is determined the properties of the dosage form and the physicochemical properties of the drug. Differences in bioavailability among formulations of a given drug can have clinical thus, knowing whether drug formulations are equivalent is essential. Bioavailability can be calculated from: f AUC (21) The AUC obtained after i. administration serves as reference and the is used when AUCs are compared that have been obtained after different doses. There are a number of potential causes for low bioavailability. Orally administered drugs must pass through the intestinal wall and then through the portal circulation to the both are common sites of metabolism (metabolism of a drug before it reaches systemic circulation). Many drugs may be metabolized before adequate plasma concentrations are reached. Low bioavailability is most common with oral dosage forms of poorly soluble, slowly absorbed drugs. Insufficient absorption time in the GI tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (eg, if it is highly ionized and polar), the time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Age, sex, physical activity, genetic phenotype, stress, disorders (eg, achlorhydria, malabsorption syndromes), or previous GI surgery can also affect drug bioavailability. A term which is related but different from is Formulations are considered in extent and rate of absorption if their plasma 20