Pharmacokinetics: Drug Absorption, Distribution, Metabolism, and Elimination PDF

Chapter 2 PASSAGE OF DRUGS ACROSS MEMBRANE BARRIERS Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination...

Chapter 2 PASSAGE OF DRUGS ACROSS MEMBRANE BARRIERS Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination Iain L. O. Buxton The Plasma Membrane Is Selectively Permeable A Few Principles of Metabolism and Elimination Prodrugs Modes of Permeation and Transport Pharmacogenetics EXCRETION OF DRUGS DRUG ABSORPTION, BIOAVAILABILITY, AND ROUTES OF Renal Excretion ADMINISTRATION Biliary and Fecal Excretion Absorption and Bioavailability Excretion by Other Routes Routes of Administration Novel Methods of Drug Delivery CLINICAL PHARMACOKINETICS Clearance BIOEQUIVALENCE Distribution Steady-State Concentration DISTRIBUTION OF DRUGS Half-Life Not All Tissues Are Equal Extent and Rate of Absorption Binding to Plasma Proteins Nonlinear Pharmacokinetics Tissue Binding Design and Optimization of Dosage Regimens METABOLISM OF DRUGS THERAPEUTIC DRUG MONITORING The human body restricts access to foreign molecules; therefore, to reach oriented outward. Individual lipid molecules in the bilayer vary accord- its target within the body and have a therapeutic effect, a drug molecule ing to the particular membrane and can move laterally and organize must cross several restrictive barriers en route to its target site. Following themselves into microdomains (e.g., regions with sphingolipids and administration, the drug must be absorbed and distributed, usually via cholesterol, forming lipid rafts), endowing the membrane with fluidity, vessels of the circulatory and lymphatic systems. In addition to cross- flexibility, functional organization, high electrical resistance, and relative ing membrane barriers, the drug must survive metabolism (primar- impermeability to highly polar molecules. Membrane proteins embed- ily hepatic) and elimination (by the kidney and liver and in the feces). ded in the bilayer serve as structural anchors, receptors, ion channels, ADME, the absorption, distribution, metabolism, and elimination of or transporters to transduce electrical or chemical signaling pathways drugs, are the processes of pharmacokinetics (Figure 2–1). Understand- and provide selective targets for drug actions. Far from being a sea of ing these processes and their interplay and employing pharmacokinetic lipids with proteins floating randomly about, membranes are ordered principles increase the probability of therapeutic success and reduce the and compartmented (Banani et al., 2017; Kitamata et al., 2020) with occurrence of adverse drug events and drug-drug interactions. structural scaffolding elements linking to the cell interior. Membrane The absorption, distribution, metabolism, and excretion of a drug proteins may be associated with caveolin and sequestered within cave- involve its passage across numerous cell membranes. Mechanisms by olae, excluded from caveolae, or organized in signaling domains rich in which drugs cross membranes and the physicochemical properties of cholesterol and sphingolipids not containing caveolin or other scaffold- molecules and membranes that influence this transfer are critical to ing proteins. understanding the disposition of drugs in the human body. The char- acteristics of a drug that predict its movement and availability at sites of Modes of Permeation and Transport action are its molecular size (i.e., molecular weight) and structural fea- Passive diffusion dominates transmembrane movement of most drugs. tures, degree of ionization, the relative lipid solubility of its ionized and However, carrier-mediated mechanisms (active transport and facilitated nonionized forms, and its binding to serum and tissue proteins. Although diffusion) play important roles (Figure 2–2; Figure 4–4). physical barriers to drug movement may be a single layer of cells (e.g., intestinal epithelium) or several layers of cells and associated extracellular Passive Diffusion In passive transport, the drug molecule usually penetrates by diffusion protein (e.g., skin), the plasma membrane is the basic barrier. along a concentration gradient by virtue of its solubility in the lipid bilayer. Such transfer is directly proportional to the magnitude of the concentration gradient across the membrane, to the lipid:water partition coefficient of the Passage of Drugs Across Membrane Barriers drug, and to the membrane surface area exposed to the drug. At steady state, the concentration of the unbound drug is the same on both sides of The Plasma Membrane Is Selectively Permeable the membrane if the drug is a nonelectrolyte. For ionic compounds, the The plasma membrane consists of a bilayer of amphipathic lipids with steady-state concentrations depend on the electrochemical gradient for their hydrocarbon chains oriented inward to the center of the bilayer the ion and on differences in pH across the membrane, which will influ- to form a continuous hydrophobic phase, with their hydrophilic heads ence the state of ionization of the molecule disparately on either side of https://ebooksmedicine.net/  24 Abbreviations is the pH at which half the drug (weak acid or base electrolyte) is in its ionized form. The ratio of nonionized to ionized drug at any pH may be calculated from the Henderson-Hasselbalch equation: ABC: ATP-binding cassette ACE: angiotensin-converting enzyme [protonated form] log = p K a − pH (Equation 2–1) AUC: area under the concentration-time curve of drug [unprotonated form] CHAPTER 2 PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION absorption and elimination BBB: blood-brain barrier Equation 2–1 relates the pH of the medium around the drug and the drug’s acid dissociation constant (pKa) to the ratio of the protonated (HA CL: clearance or BH+) and unprotonated (A− or B) forms, where CNS: central nervous system CNT1: concentrative nucleoside transporter 1 [A − ][H+ ] Cp: plasma concentration HA ↔ A − + H+ , where K a = [HA] CSF: cerebrospinal fluid Css: steady-state concentration describes the dissociation of an acid, and CYP: cytochrome P450 F: bioavailability [B][H+ ] BH+ ↔ B + H+ , where K a = FDA: Food and Drug Administration [BH+ ] GI: gastrointestinal h: hours describes the dissociation of the protonated form of a base. k: a rate constant At steady state, an acidic drug will accumulate on the more basic side MDR1: multidrug resistance protein of the membrane and a basic drug on the more acidic side. This phenom- MEC: minimum effective concentration enon, known as ion trapping, is an important process in drug distribution min: minutes with potential therapeutic benefit and in management of the poisoned PLLR: Pregnancy and Lactation Labeling Rule patient (Ornillo and Harbord, 2020). Figure 2–3 illustrates this effect and SLC: solute carrier shows the calculated values for the distribution of a weak acid between T, t: time the plasma and gastric compartments. t1/2: half-life The effects of pH on transmembrane partitioning can be utilized to V: volume of distribution alter drug excretion. In the kidney tubules, urine pH can vary over a wide Vss: volume of distribution at steady state range, from 4.5 to 8. As urine pH drops (as [H+] increases), weak acids (A–) and weak bases (B) will exist to a greater extent in their protonated forms (HA and BH+); the reverse is true as pH rises, where A– and B will be favored. Thus, alkaline urine favors excretion of weak acids; acidic the membrane and can effectively trap ionized drug on one side of the urine favors excretion of weak bases. Elevation of urine pH (by giving membrane. sodium bicarbonate) will promote urinary excretion of weak acids such Influence of pH on Ionizable Drugs as aspirin (pKa ~3.5) and urate (pKa ~5.8). Another useful consequence Many drugs are weak acids or bases that are present in solution as both of a drug being ionized at physiological pH is illustrated by the relative the lipid-soluble, diffusible nonionized form and the ionized species that lack of sedative effects of second-generation histamine H1 antagonists is relatively lipid insoluble and poorly diffusible across a membrane. (e.g., loratadine): Second-generation antihistamines are ionized molecules Common ionizable groups are carboxylic acids and amino groups (pri- (less lipophilic, more hydrophilic) that poorly cross the BBB compared to mary, secondary, and tertiary; quaternary amines hold a permanent pos- first-generation agents such as diphenhydramine, which are now used as itive charge). The transmembrane distribution of a weak electrolyte is sleep aids. Also of note, most bacterial urinary tract infections cause the influenced by its pKa and the pH gradient across the membrane. The pKa urine to become alkaline, potentially altering therapy (Huang et al., 2020). TISSUE RESERVOIRS bound free THERAPEUTIC UNWANTED SITE SITE OF ACTION OF ACTION “Receptors” CENTRAL bound free bound free COMPARTMENT ABSORPTION CLEARANCE DRUG [FREE DRUG] DOSE LIBERATION EXCRETION protein bound metabolites drug BIOTRANSFORMATION Figure 2–1 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possible distribution and binding of metabolites in relation to their potential actions at receptors are not depicted.  ACTIVE TRANSPORT 25 PASSIVE TRANSPORT Primary Secondary Paracellular Diffusion Facilitated Na+ X Na+ Y transport diffusion K+ SECTION I [Na+] ~ 140 mm [K+] ~ 4 mm +++ out anti sym ––– in ATP [Na+] ~ 10 mm [K+] ~ 150 mm ADP Na+ X Na+ Y GENERAL PRINCIPLES + K+ Pi SLC ABC Na+,K+ - SLC co-transporters transporter transporter ATPase Figure 2–2 Drugs move across membrane and cellular barriers in a variety of ways. See details in Figures 4–1 through 4–4. Carrier-Mediated Membrane Transport of heart failure (see Chapter 29). A group of primary active transporters, Proteins in the plasma membrane mediate transmembrane movements of the ABC family, hydrolyze ATP to export substrates across membranes. many physiological solutes; these proteins also mediate transmembrane For example, the P-glycoprotein, also called ABCB1 or MDR1, exports movements of drugs and can be targets of drug action. Mediated trans- bulky neutral or cationic compounds from cells; its physiologic substrates port is broadly characterized as facilitated diffusion or active transport include steroid hormones such as testosterone and progesterone. MDR1 (see Figure 2–2; Figure 4–4). Membrane transporters and their roles in exports many drugs as well, including digoxin, and a great variety of drug response are presented in detail in Chapter 4. other agents (see Table 4–4). P-glycoprotein in the enterocyte limits the absorption of some orally administered drugs by exporting compounds Facilitated Diffusion. Facilitated diffusion is a carrier-mediated into the lumen of the GI tract subsequent to their absorption (Gessner transport process in which the driving force is simply the electro- et al., 2019). ABC transporters perform a similar function in the cells of chemical gradient of the transported solute; thus, these carriers can the BBB, effectively reducing net accumulation of some compounds in the facilitate solute movement either in or out of cells, depending on the brain (see Chapters 4 and 17). By the same mechanism, P-glycoprotein direction of the electrochemical gradient. The carrier protein may be also can confer resistance to some cancer chemotherapeutic agents highly selective for a specific conformational structure of an endoge- (see Chapters 69–73). nous solute or a drug whose rate of transport by passive diffusion Members of the SLC superfamily can mediate secondary active trans- through the membrane would otherwise be quite slow. For instance, port using the electrochemical energy stored in a gradient (usually Na+) the organic cation transporter OCT1 (SLC22A1) facilitates the move- to translocate both biological solutes and drugs across membranes. For ment of a physiologic solute, thiamine (Jensen et al., 2020), and drugs, instance, the Na+/Ca2+ exchange protein (SLC8 or NCX) uses the energy including metformin, which is used in treating type 2 diabetes. Chapter 4 stored in the Na+ gradient established by Na+/K+-ATPase to export cyto- describes OCT1 and other members of the human SLC superfamily solic Ca2+ and maintain it at a low basal level, about 100 nM in most of transporters. cells. SLC8 is thus an antiporter, using the inward flow of Na+ to drive an Active Transport. Active transport is characterized by a direct require- outward flow of Ca2+. SLC8 also helps to mediate the positive inotropic ment for energy, capacity to move solute against an electrochemical effects of digoxin and other cardiac glycosides that inhibit the activity of gradient, saturability, selectivity, and competitive inhibition by cotrans- Na+/K+-ATPase and thereby reduce the driving force for the extrusion ported compounds. Na+/K+-ATPase is an important example of an active of Ca2+ from the ventricular cardiac myocyte. Other SLC cotransport- transport mechanism, which simultaneously exports three sodium ions ers are symporters, in which the driving force ion and solute move in in exchange for two potassium ions using ATP as the energy substrate. the same direction. The CNT1 (SLC28A1), driven by the Na+ gradi- Digoxin is an important Na+/K+-ATPase inhibitor used in the treatment ent, moves pyrimidine nucleosides and the cancer chemotherapeutic agents gemcitabine and cytarabine into cells. DAT, NET, and SERT, pKa = 4.4 1001 = [HA] + [A–] transporters for the neurotransmitters dopamine, norepinephrine, and – + serotonin, respectively, are secondary active transporters that also rely HA A+H on the energy stored in the transmembrane Na+ gradient. These sym- Plasma pH = 7.4 porters coordinate movement of Na+ and neurotransmitter in the same direction (into the neuron). DAT, NET, and SERT are also the targets of Lipid Mucosal Barrier CNS-active agents used to treat depression and/or anxiety. Members of Gastric juice pH = 1.4 the SLC superfamily are active in drug transport in the GI tract, liver, and kidney, among other sites, and play a significant role in drug disposition [0.001] 1.001 = [HA] + [A–] (Liu, 2019). – + HA A+H Paracellular Transport Figure 2–3 Influence of pH on the distribution of a weak acid (pKa = 4.4) In the vascular compartment, paracellular passage of solutes and fluid between plasma and gastric juice separated by a lipid barrier. A weak acid through intercellular gaps is sufficiently large that passive transfer across dissociates to different extents in plasma (pH 7.4) and gastric acid (pH 1.4): the endothelium of capillaries and postcapillary venules is generally lim- The higher pH facilitates dissociation; the lower pH reduces dissociation. The ited by blood flow. Evidence of this phenomenon can readily be seen in uncharged form, HA, equilibrates across the membrane. Blue numbers in the dependent edema that forms in the ankles of heart failure patients. brackets show relative equilibrium concentrations of HA and A−, as calculated Capillaries of the CNS and a variety of epithelial tissues have tight junc- from Equation 2–1. tions that limit paracellular movement of drugs (Spector et al., 2015). https://ebooksmedicine.net/  26 Factors modifying bioavailability also apply to prodrugs, in which case Drug Absorption, Bioavailability, and Routes availability results from metabolic processes that produce the active form of Administration of the drug. Absorption and Bioavailability Routes of Administration Some characteristics of the major administration routes employed for CHAPTER 2 PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION Absorption is the movement of a drug from its site of administration into the central compartment (e.g., bloodstream; see Figure 2–1). For systemic drug effect are compared in Table 2–1. solid dosage forms, absorption first requires dissolution of the tablet or Oral Administration capsule, thus liberating the drug. Except in cases of malabsorption syn- Oral ingestion is the most common method of drug administration. It dromes, the clinician is concerned primarily with bioavailability rather also is the safest, most convenient, and most economical. Its disadvan- than absorption (Tran et al., 2013). tages include limited absorption of some drugs because of their physical Bioavailability describes the fractional extent to which an adminis- characteristics (e.g., low water solubility or poor membrane permeabil- tered dose of drug reaches its site of action or a biological fluid (usually ity), emesis as a result of irritation to the GI mucosa, destruction of some the systemic circulation) from which the drug has access to its site of drugs by digestive enzymes or low gastric pH, irregularities in absorp- action. A drug given orally must be absorbed first from the GI tract, tion or propulsion in the presence of food or other drugs, and the need but net absorption may be limited by the characteristics of the dosage for cooperation on the part of the patient. In addition, drugs in the GI form, by the drug’s physicochemical properties, by metabolic attack tract may be metabolized by the enzymes of the intestinal microbiome, in the intestine, and by transport across the intestinal epithelium and mucosa, or liver before they gain access to the general circulation. The into the portal circulation. The absorbed drug then passes through gut microbiome comprises over 1000 species; its alteration may impact the liver, where metabolism and biliary excretion may occur before the disease progression and therapeutic outcomes (see Chapter 6 and drug enters the systemic circulation. Accordingly, less than all of the Ding et al., 2020). administered dose may reach the systemic circulation and be distrib- Absorption from the GI tract is governed by factors such as surface uted to the drug’s sites of action. If the metabolic or excretory capacity area for absorption; blood flow to the site of absorption; the physical state of the liver and the intestine for the drug is large, bioavailability will be of the drug (solution, suspension, or solid dosage form); its aqueous sol- reduced substantially (first-pass effect). This decrease in availability is ubility; and the drug’s concentration at the site of absorption. For drugs a function of the anatomical site from which absorption takes place; given in solid form, the rate of dissolution may limit their absorption. for instance, intravenous administration generally permits all of a drug Because most drug absorption from the GI tract occurs by passive dif- to enter the systemic circulation. Other anatomical, physiological, and fusion, absorption is favored when the drug is in the nonionized, more pathological factors can influence bioavailability (described further in lipophilic form. Based on the pH-partition concept (see Figure 2–3), one this chapter), and the route of drug administration should be chosen would predict that drugs that are weak acids would be better absorbed based on an understanding of these conditions. We can define bioavail- from the stomach (pH 1–2) than from the upper intestine (pH 3–6), and ability F as: vice versa for weak bases. However, the surface area of the stomach is relatively small, and a mucus layer covers the gastric epithelium. By con- Quantity of drug reaching systemic circulation trast, the villi of the upper intestine provide an extremely large surface area F= (Equation 2–2) Quantity of drug administered (~200 m2). Accordingly, the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predom- where 0 < F ≤ 1. inantly ionized in the intestine and largely nonionized in the stomach. TABLE 2–1 SOME CHARACTERISTICS OF COMMON ROUTES OF DRUG ADMINISTRATIONa ROUTE AND BIOAVAILABILTY (F) ABSORPTION PATTERN SPECIAL UTILITY LIMITATIONS AND PRECAUTIONS Intravenous Absorption circumvented Valuable for emergency use Increased risk of adverse effects F = 1 by definition Potentially immediate effects Permits titration of dosage Must inject solutions slowly as a rule Suitable for large volumes and for Usually required for high-molecular- Not suitable for oily solutions or poorly irritating substances, or complex weight protein and peptide drugs soluble substances mixtures, when diluted Subcutaneous Prompt from aqueous solution Suitable for some poorly soluble Not suitable for large volumes 0.75 < F < 1 suspensions and for instillation of slow- release implants Slow and sustained from Possible pain or necrosis from irritating repository preparations substances Intramuscular Prompt from aqueous solution Suitable for moderate volumes, oily Precluded during anticoagulant therapy 0.75 < F < 1 vehicles, and some irritating substances Slow and sustained from Appropriate for self-administration (e.g., May interfere with interpretation of repository preparations insulin) certain diagnostic tests (e.g., creatine kinase) Oral ingestion Variable, depends on many Most convenient and economical; usually Requires patient compliance 0.05 < F < 1 factors (see text) safer Bioavailability potentially erratic and incomplete See text for more complete discussion and for other routes. a Thus, any factor that accelerates gastric emptying (recumbent position indiscriminate diffusion of molecules regardless of their lipid solubility. 27 right side) will generally increase the rate of drug absorption, whereas Larger molecules, such as proteins, slowly gain access to the circulation any factor that delays gastric emptying will have the opposite effect. by way of lymphatic channels. Drugs administered into the systemic cir- The gastric emptying rate is influenced by numerous factors, including culation by any route, excluding the intra-arterial route, are subject to the caloric content of food; volume, osmolality, temperature, and pH of possible first-pass elimination in the lung prior to distribution to the rest SECTION I ingested fluid; diurnal and interindividual variation; metabolic state (rest of the body. The lungs also serve as a filter for particulate matter that or exercise); and the ambient temperature. Gastric emptying is influenced may be given intravenously and provide a route of elimination for volatile in women by the effects of estrogen (i.e., compared to men, emptying is substances. slower for premenopausal women and those taking estrogen replacement Intravenous. Factors limiting absorption are circumvented by intra- therapy). venous injection of drugs in aqueous solution because bioavailability is Drugs that are destroyed by gastric secretions and low pH or that cause complete (F = 1.0) and distribution is rapid. Also, drug delivery is con- gastric irritation sometimes are administered in dosage forms with an trolled and achieved with an accuracy and immediacy not possible by GENERAL PRINCIPLES enteric coating that prevents dissolution in the acidic gastric contents. any other procedures. Certain irritating solutions can be given only in Enteric coatings are useful for drugs that can cause gastric irritation and this manner because the drug, when injected slowly, is greatly diluted by for presenting a drug such as mesalamine to sites of action in the ileum the blood. and colon (see Figure 55–4). There are advantages and disadvantages to intravenous administra- Controlled-Release Preparations. The rate of absorption of a drug tion. Unfavorable reactions can occur because high concentrations of administered as a tablet or other solid oral dosage form is partly depen- drug may be attained rapidly in plasma and tissues. There are therapeu- dent on its rate of dissolution in GI fluids. This is the basis for con- tic circumstances for which it is advisable to administer a drug by bolus trolled-release, extended-release, sustained-release, and prolonged-action injection (e.g., tissue plasminogen activator) and other circumstances pharmaceutical preparations that are designed to produce slow, uniform where slower or prolonged administration of drug is advisable (e.g., anti- absorption of the drug for 8 h or longer. Potential advantages of such biotics). Intravenous administration of drugs warrants careful determi- preparations are reduction in the frequency of administration compared nation of dose and close monitoring of the patient’s response; once the with conventional dosage forms (often with improved compliance by the drug is injected, there is often no retreat. Repeated intravenous injections patient), maintenance of a therapeutic effect overnight, and decreased depend on the ability to maintain a patent vein. Drugs in an oily vehi- incidence and intensity of undesired effects (by dampening of the peaks cle, those that precipitate blood constituents or hemolyze erythrocytes, in drug concentration) and nontherapeutic blood levels of the drug (by and drug combinations that cause precipitates to form must not be given elimination of troughs in concentration) that often occur after admin- intravenously. istration of immediate-release dosage forms. Controlled-release dosage Subcutaneous. Injection into a subcutaneous site can be done only forms are most appropriate for drugs with short half-lives (t1/2 6 mL/min/ function), the rate of elimination of cephalexin will depend on the con- kg, such as diltiazem, imipramine, lidocaine, morphine, and propranolol) centration of drug in the plasma (see Equation 2–5). are restricted in their rate of elimination not by intrahepatic processes, The β adrenergic receptor antagonist propranolol is cleared from the GENERAL PRINCIPLES but by the rate at which they can be transported in the blood to the liver. blood at a rate of 16 mL/min/kg (or 1600 mL/min in a 100-kg man), Pharmacokinetic models indicate that when the capacity of the elim- almost exclusively by the liver. Thus, the liver is able to remove the inating organ to metabolize the drug is large in comparison with the amount of propranolol contained in 1600 mL of blood in 1 min, roughly rate of presentation of drug to the organ, clearance will approximate the equal to total hepatic blood flow (see Table 2–2). In fact, the plasma clear- organ’s blood flow. By contrast, when the drug-metabolizing capacity is ance of some drugs exceeds the rate of blood flow to this organ. Often, small in comparison with the rate of drug presentation, clearance will this is so because the drug partitions readily into and out of red blood be proportional to the unbound fraction of drug in blood (funb) and the cells (rbc), and the rate of drug delivered to the eliminating organ is con- drug’s intrinsic clearance (CLint), where intrinsic clearance represents siderably higher than expected from measurement of its concentration drug binding to components of blood and tissues or the intrinsic capacity in plasma. The relationship between plasma clearance (CLp) and blood of the liver to eliminate a drug in the absence of limitations imposed by clearance (CLb; all components of blood) at steady state is given by blood flow (Guner and Bowen, 2013). Thus, hepatic clearance will be: CLp Cb C  QH (fumb )(CLint ) = =1+ H  rbc − 1 (Equation 2–8) CLH = (Equation 2–11) CLb C p  C p  QH + (fumb )(CLint ) Clearance from the blood therefore may be estimated by dividing the Renal Clearance plasma clearance by the drug’s blood-to-plasma concentration ratio, Renal clearance of a drug results in its appearance in the urine. In con- obtained from knowledge of the hematocrit (H = 0.45) and concentration sidering the clearance of a drug from the body by the kidney, glomerular ratio of red cells to plasma. In most instances, the blood clearance will be filtration, secretion, reabsorption, and glomerular blood flow must be less than liver blood flow (1.5–1.7 L/min) or, if renal excretion is involved, considered (see Figure 2–5). The rate of filtration of a drug depends on the the sum of the blood flows to each eliminating organ. For example, the volume of fluid that is filtered in the glomerulus and the concentration of plasma clearance of the immunomodulator tacrolimus, about 2 L/min, unbound drug in plasma (because drug bound to protein is not filtered). is more than twice the hepatic plasma flow rate and even exceeds the The rate of secretion of drug into the tubular fluid is the largest factor organ’s blood flow despite the fact that the liver is the predominant site determining renal excretion. Secretion will depend on the transporters of this drug’s extensive metabolism. However, after taking into account involved in active secretion as affected by the drug’s binding to plasma the extensive distribution of tacrolimus into red cells, its clearance from proteins, the degree of saturation of these transporters, the rate of delivery the blood is only about 63 mL/min, and it is actually a drug with a rather of the drug to the secretory site, and the presence of drugs that can com- low clearance, not a high-clearance agent as might be expected from the pete for these transporters. In addition, one must consider processes of plasma clearance value alone. Clearance from the blood by metabolism drug reabsorption from the tubular fluid back into the bloodstream such can exceed liver blood flow, and this indicates extrahepatic metabolism. as occurs with uric acid. The influences of changes in protein binding, In the case of the β1 receptor antagonist esmolol, the blood clearance value blood flow, and the functional state of nephrons will affect renal clearance. (11.9 L/min) is greater than cardiac output (~5.5 L/min) because the drug Aspirin demonstrates the interplay among renal absorption and secre- is metabolized efficiently by esterases present in red blood cells. tion. Aspirin has a bimodal effect on the renal handling of uric acid: High A further definition of clearance is useful for understanding the effects doses of aspirin (>3 g/day) are uricosuric (probably by blocking urate of pathological and physiological variables on drug elimination, particu- reabsorption), while low dosages (1–2 g/day) cause uric acid retention larly with respect to an individual organ. The rate of presentation of drug (probably via inhibiting urate secretion). Low-dose aspirin, indicated for to the organ is the product of blood flow Q and the arterial drug concen- the prophylaxis of cardiovascular events, can cause changes in renal func- tration CA, and the rate of exit of drug from the organ is the product of tion and uric acid handling in elderly patients. blood flow and the venous drug concentration CV. The difference between these rates at steady state is the rate of drug elimination by that organ: Distribution Volume of Distribution Rate of elimination = Q ⋅ C A − Q ⋅ C V The volume of distribution V relates the amount of drug in the body to (Equation 2–9) the concentration of drug C in the blood or plasma, depending on the = Q( C A − C V ) fluid measured. This volume does not necessarily refer to an identifi- able physiological volume, but rather to the fluid volume that would be Dividing Equation 2–8 by the concentration of drug entering the organ required to contain all of the drug in the body at the same concentration of elimination, CA, yields an expression for clearance of the drug by the measured in the blood or plasma: organ in question: Amount of drug in body/V = C C −C  or CLorgan = Q  A V  = Q × E (Equation 2–10)  CA  V = Amount of drug in body/C (Equation 2–12) The expression (CA – CV)/CA in Equation 2–10 can be referred to as the View V as an imaginary volume because for many drugs V exceeds the extraction ratio E of the drug. While not employed in general medi- known volume of any and all body compartments (Box 2–1). For exam- cal practice, calculations of a drug’s extraction ratio(s) are useful for ple, the value of V for the highly lipophilic antimalarial chloroquine is https://ebooksmedicine.net/  34 BOX 2–1 V Values > Any Physiological Volume? The volume of distribution defined in Equation 2–12 considers the body as a single homogeneous compartment. In this one-compartment For many drugs, Equation 2–12 will give V values that exceed any model, all drug administration occurs directly into the central compart- physiological volume. For example, if 500 μg of the cardiac glycoside ment, and distribution of drug is instantaneous throughout the volume V. digoxin were added into the body of a 70-kg subject, a plasma Clearance of drug from this compartment occurs in a first-order fashion, concentration of about 0.75 ng/mL would be observed. Dividing as defined in Equation 2–5; that is, the amount of drug eliminated per CHAPTER 2 PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION the amount of drug in the body by the plasma concentration yields unit of time depends on the amount (concentration) of drug in the body a volume of distribution for digoxin of about 667 L, or a value about compartment at that time. Figure 2–6A and Equation 2–9 describe the 15 times greater than the total-body volume of a 70-kg man. In decline of plasma concentration with time for a drug introduced into this fact, digoxin distributes preferentially to muscle and adipose tissue central compartment: and binds to its specific receptors, the Na+/K+-ATPase, leaving a very small amount of drug in the plasma to be measured. A drug’s  Dose  − kt C= [e ] (Equation 2–13) volume of distribution therefore can reflect the extent to which it is  V  present in extravascular tissues and not in the plasma. Conversely, a small value for V can indicate maintenance of the drug in the where k is the rate constant for elimination that reflects the fraction of bloodstream desirable in the treatment of leukemias. Many newer drug removed from the compartment per unit of time. This rate constant drug formulations encapsulate one or more drugs in liposomes or is inversely related to the t1/2 of the drug [kt1/2 = ln 2 = 0.693]. The ideal- engineered nanoparticles to regulate drug distribution (Filipczak et al., ized one-compartment model does not describe the entire time course of 2020). Thus, V may vary widely depending on the relative degrees the plasma concentration. Certain tissue reservoirs can be distinguished of binding to high-affinity receptor sites, plasma and tissue proteins, from the central compartment, and the drug concentration appears to the partition coefficient of the drug in fat, accumulation in poorly decay in a manner that can be described by multiple exponential terms perfused tissues, and engineered strategies such as encapsulation. (Figure 2–6B). The volume of distribution for a given drug can differ according to a patient’s age, gender, body composition, and presence of disease. Rates of Distribution Total-body water of infants younger than 1 year of age, for example, In many cases, groups of tissues with similar perfusion-to-partition ratios is 75% to 80% of body weight, whereas that of adult males is 60% and all equilibrate at essentially the same rate such that only one apparent that of females is 55%. phase of distribution is seen (rapid initial decrease in concentration of intravenously injected drug, as in Figure 2–6B). Essentially, the drug starts in a “central” volume (see Figure 2–1), which consists of plasma and approximately 15,000 L, whereas the volume of total-body water is about tissue reservoirs that are in rapid equilibrium, then distributes to a “final” 42 L in a 70-kg male. The benefit of determining V is to understand dis- volume, at which point concentrations in plasma decrease in a log-linear tribution of drug to the body away from the bloodstream as an indication fashion with a rate constant of k (see Figure 2–6B). The multicompart- of its distribution to sites of action. ment model of drug disposition can be viewed as though the blood and For drugs that are bound extensively to plasma proteins but are not highly perfused lean organs such as heart, brain, liver, lung, and kidneys bound to tissue components, the volume of distribution will approach that cluster as a single central compartment, whereas more slowly perfused of the plasma volume because drug bound to plasma protein is measurable tissues such as muscle, skin, fat, and bone behave as the final compart- in the assay of most drugs. In contrast, certain drugs have high volumes of ment (the tissue compartment). distribution even though most of the drug in the circulation is bound to If blood flow to certain tissues changes within an individual, rates of albumin because these drugs are sequestered elsewhere in the body. drug distribution to these tissues also will change. Changes in blood flow A B 32 32 C 0 p C0p = 31 Plasma Drug Concentration 16 Plasma Drug Concentration 16 V = Dose/C0p 8 8 (µg/mL) (µg/mL) 4 4 2 2 t1/ t1/2 2 1 1 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Time (hours) Time (hours) Figure 2–6 Plasma concentration-time curves following intravenous administration of a drug (500 mg) to a 70-kg patient. A. Drug concentrations are measured in plasma at 2-h intervals following drug administration. The semilogarithmic plot of plasma concentration Cp versus time suggests that the drug is eliminated from a single compartment by a first-order process (see Equation 2–13) with a t1/2 of 4 h (k = 0.693/t1/2 = 0.173 h1). The volume of distribution V may be deter- mined from the value of Cp obtained by extrapolation to zero-time. Volume of distribution (see Equation 2–12) for the one-compartment model is 31.3 L, or 0.45 L/kg (V = dose/C 0p). The clearance for this drug is 90 mL/min; for a one-compartment model, CL = kV. B. Sampling before 2 h indicates that the drug follows multiexponential kinetics. The terminal disposition t1/2 is 4 h, clearance is 84 mL/min (see Equation 2–7), and Vss is 26.8 L (see Equation 2–14). The initial or “central” distribution volume for the drug (V = dose/C 0p) is 16.1 L. The example indicates that multicompartment kinetics may be overlooked when sampling at early times is neglected. In this particular case, there is only a 10% error in the estimate of clearance when the multicompartment characteristics are ignored. For many drugs, multicompartment kinetics may be observed for significant periods of time, and failure to consider the distribution phase can lead to significant errors in estimates of clearance and in predictions of appropriate dosage. may cause some tissues that were originally in the “central” volume to 2 Steady State 35 equilibrate sufficiently more slowly so they appear only in the “final” vol- Attained after approximately four half-times ume. This means that central volumes will appear to vary with disease Time to steady state independent of dosage states that cause altered regional blood flow (such as would be seen in cir- rhosis of the liver). After an intravenous bolus dose, drug concentrations Css SECTION I in plasma may be higher in individuals with poor perfusion (e.g., shock) Concentration than they would be if perfusion were better. These higher systemic con- centrations may in turn cause higher concentrations (and greater effects) 1 in tissues such as brain and heart, whose usually high perfusion has not been reduced. Thus, the effect of a drug at various sites of action can vary Steady-State Concentrations depending on perfusion of these sites. Proportional to dose/dosage interval Proportional to F/CL Multicompartment Volumes GENERAL PRINCIPLES Fluctuations In multicompartment kinetics, a volume of distribution term is useful Proportional to dose interval/half-time especially when the effect of disease states on pharmacokinetics is to be Blunted by slow absorption 0 determined. The volume of distribution at steady-state Vss represents the 0 1 2 3 4 5 6 volume in which a drug would appear to be distributed during steady state if the drug existed throughout that volume at the same concen- Time (multiples of elimination half-time) tration as that in the measured fluid (plasma or blood). Vss also may be Figure 2–7 Fundamental pharmacokinetic relationships for repeated admin- appreciated as shown in Equation 2–14, where VC is the volume of distri- istration of drugs. The red line is the pattern of drug accumulation during bution of drug in the central compartment and VT is the volume term for repeated administration of a drug at intervals equal to its elimination half- drug in the tissue compartment: time. With instantaneous absorption, each dose would add 1 concentration unit to Cp at the time of administration, and then half of that would be elimi- Vss = VC + VT (Equation 2–14) nated prior to administration of the next dose, resulting in the oscillation of Cp between 1 and 2 after four or five elimination half-times. However, this more Steady-State Concentration realistic simulation uses a rate of drug absorption that is not instantaneous but Equation 2–3 (Dosing rate = CL · Css) indicates that a steady-state concen- is 10 times as rapid as elimination; drug is eliminated throughout the absorp- tration eventually will be achieved when a drug is administered at a con- tion process, blunting the maximal blood level achieved after each dose. With stant rate. At this point, drug elimination (the product of clearance and repeated administration, Cp achieves steady state, oscillating around the blue concentration; Equation 2–5) will equal the rate of drug availability. This line at 1.5 units. The blue line depicts the pattern during administration of equivalent dosage by continuous intravenous infusion. Curves are based _ on concept also extends to regular intermittent dosage (e.g., 250 mg of drug the one-compartment model. Average drug concentration at steady state Css is: every 8 h). During each interdose interval, the concentration of drug rises with absorption and falls by elimination. At steady state, the entire cycle F ⋅ dose F ⋅ dosing rate is repeated identically in each interval (Figure 2–7). Equation 2–3 still C ss = = CL ⋅ T CL applies for intermittent dosing, but it now describes the average steady- state drug concentration _ during an interdose interval. Note the extension where the dosing rate is the dose per time interval and is dose/T, F is the of this idea to derive Css during continuous intravenous drug infusion, as fractional bioavailability, and CL is clearance. Note that substitution of explained in the legend to Figure 2–7. infusion rate for [F ⋅ dose/T] provides the concentration maintained at steady state during continuous intravenous infusion (F = 1 with intrave- Half-Life nous administration). The t1/2 is the time it takes for the plasma concentration of drug to be reduced by 50%. For the one-compartment model of Figure 2–6A, t1/2 may this accumulation can result in toxicity). Biliary cycling probably is be determined readily by inspection of the data and used to make deci- responsible for the 120-h terminal value for indomethacin (compared to sions about drug dosage. However, as indicated in Figure 2–6B, drug con- the steady-state value of 2.4 h). Intravenous anesthetics provide a good centrations in plasma often follow a multicomponent pattern of decline. example; many have context-sensitive half-times; these agents, with short half-times after single intravenous doses, exhibit longer half-times in pro- Half-Life, Volume of Distribution, and Clearance portion to the duration of exposure when used in maintenance anesthesia When using pharmacokinetics to calculate drug dosing in disease, note (see Figure 21–2). that t1/2 changes as a function of both clearance and volume of distribution: Clearance is the measure of the body’s capacity to eliminate a drug. t1/2 ≅ 0.693 · Vss/CL (Equation 2–15) Thus, as clearance decreases, owing to a disease process for example, t1/2 will increase as long as the volume of distribution remains unchanged. This t1/2 reflects the decline of systemic drug concentrations during a Alternately, the volume of distribution may change, but CL remains con- dosing interval at steady state as depicted in Figure 2–7. stant or both can change. For example, the t1/2 of diazepam increases with increasing age; however, this does not reflect a change in clearance, but Terminal Half-Life rather a change in the volume of distribution. Similarly, changes in protein With prolonged dosing (or with high drug concentrations), a drug may binding of a drug (e.g., hypoalbuminemia) may affect its clearance as well penetrate beyond the central compartment into “deep” or secondary as its volume of distribution, leading to unpredictable changes in t1/2 as a body compartments that equilibrate only slowly with the plasma. When function of disease. The t1/2 defined in Equation 2–15 provides an approx- the infusion or dosing stops, the drug will be initially cleared from plasma imation of the time required to reach steady state after a dosage regimen as expected. Then the concentration will drop to a point at which net is initiated or changed (e.g., four half-lives to reach ~94% of a new steady diffusion from the secondary compartments begins, and this slow equil- state). ibration will produce a prolongation of the half-life of the drug, referred to as the terminal half-life. Extent and Rate of Absorption Steady-State t1/2 and Terminal t1/2 Compared Bioavailability Examples of drugs with marked differences in terminal t1/2 versus It is important to distinguish between the amount of drug that is admin- steady-state t1/2 are gentamicin and indomethacin. Gentamicin has a t1/2 istered and the quantity of drug that ultimately reaches the systemic of 2 to 3 h following a single administration, but a terminal t1/2 of 53 h circulation. Dissolution and absorption of drug may be incomplete; https://ebooksmedicine.net/ because drug accumulates in spaces such as kidney parenchyma (where some drug may be destroyed prior to entering the systemic circulation,  36 especially by hepatic first-pass metabolism. The first-pass effect is Saturable Protein Binding extensive for many oral medications that enter the portal vein and pass As the molar concentration of small drug molecules increases, the directly to the liver. The fraction of a dose F that is absorbed and escapes unbound fraction eventually also must increase (as all binding sites first-pass elimination measures the drug’s bioavailability; thus, 0 < F ≤ 1 become saturated when drug concentrations in plasma are in the range (see Equation 2–2). of tens to hundreds of micrograms per milliliter). For a drug that is For some drugs, extensive first-pass metabolism precludes their use as metabolized by the liver with a low intrinsic clearance-extraction ratio, CHAPTER 2 PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION oral agents (e.g., lidocaine, naloxone), while other agents, though admin- saturation of plasma-protein binding will cause both V and CL to increase istered orally, must be given to avoid hepatic metabolism (e.g., glyceryl as drug concentrations increase; t1/2 thus may remain constant (see trinitrate) or can be dosed to account for the large first-pass effect (e.g., Equation 2–15). For such a drug, Css will not increase linearly as the rate propranolol). For other agents, the extent of absorption may be very low, of drug administration is increased. For drugs that are cleared with high thereby reducing bioavailability. When drugs are administered by a route intrinsic clearance-extraction ratios, Css can remain linearly proportional that is subject to significant first-pass loss or incomplete absorption, the to the rate of drug administration. In this case, hepatic clearance will not equations presented previously that contain the terms dose or dosing rate change, and the increase in V will increase the half-time of disappearance (see Equations 2–3, 2–7, and 2–13) also must include the bioavailability by reducing the fraction of the total drug in the body that is delivered to term F such that the available dose or dosing rate is used (Box 2–2). For the liver per unit of time. Most drugs fall between these two extremes. example, Equation 2–2 is modified to Saturable Elimination F · Dosing rate = CL · Css (Equation 2–16) In the case of saturable elimination, the Michaelis-Menten equation (see Equation 2–4) usually describes the nonlinearity. All active processes where the value of F is between 0 and 0.85. are undoubtedly saturable, but they will appear to be linear if values of drug concentrations encountered in practice are at or less than Km for that process (Box 2–3). When drug concentrations exceed Km, nonlin- Rate of Absorption ear kinetics are observed. Saturable metabolism causes oral first-pass The rate of absorption can be important with a drug given as a single metabolism to be less than expected (higher fractional bioavailability), dose, such as a sleep-inducing medication that must act in a reasonable time frame and achieve an effective blood level that is maintained for an BOX 2–3 Saturable Metabolism: Phenytoin appropriate duration. However, with periodic and repeated dosing, the rate of drug absorption does not, in general, influence the average steady- The antiseizure medication phenytoin is a drug for which metabolism state concentration of the drug in plasma, provided the drug is stable can become saturated by levels of the drug in the therapeutic range. before it is absorbed; the rate of absorption may, however, still influence Factors contributing to this are phenytoin’s variable half-life and drug therapy. If a drug is absorbed rapidly (e.g., a dose given as an intra- clearance and an effective concentration that varies and can saturate venous bolus) and has a small “central” volume, the concentration of clearance mechanisms, such that the Css may be saturating clearance drug initially will be high. It will then fall as the drug is distributed to its mechanisms or be well above or below that value. The t1/2 of phenytoin is “final” (larger) volume (see Figure 2–6B). If the same drug is absorbed 6 to 24 h. For clearance, Km (5–10 mg/L) is typically near the lower end more slowly (e.g., by slow infusion), a significant amount of the drug will of the therapeutic range (10–20 mg/L). For some individuals, especially be distributed while it is being administered, and peak concentrations young children and newborns being treated for emergent seizures, Km will be lower and will occur later. Controlled-release oral preparations may be as low as 1 mg/L. Consider an extreme case of a 70-kg adult in are designed to provide a slow and sustained rate of absorption to pro- whom the target concentration (Css) is 15 mg/L, Km is 1 mg/L, and the duce smaller fluctuations in the plasma concentration-time profile during maximal elimination rate, νm (from Appendix I), is 5.9 mg/kg per day, the dosage interval compared with more immediate-release formulations. or 413 mg/day per 70 kg. Substituting into Equation 2–17: