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DRUG ABSORPTION, DISTRIBUTION AND ELIMINATION;
PHARMACOKINETICS
I. DRUG ADMINISTRATION
Often the goal is to attain a therapeutic drug concentration in plasma from which drug enters the tissue (therapeutic window between toxic concentration and minimal effective concentration).
A. Enteral Routes
- Sublingual (buccal) Certain drugs are best given beneath the tongue or retained in the cheek pouch and are absorbed from these regions into the local circulation. These vascular areas are ideal for lipid-soluble drugs that would be metabolized in the gut or liver, since the blood vessels in the mouth bypass the liver (do not undergo first pass liver metabolism), and drain directly into the systemic circulation. This route is usually reserved for nitrates and certain hormones.
- Oral By far the most common route. The passage of drug from the gut into the blood is influenced by biologic and physicochemical factors (discussed in detail below), and by the dosage form. For most drugs, two- to five-fold differences in the rate or extent of gastrointestinal absorption can occur, depending on the dosage form. These two characteristics, rate and completeness of absorption, comprise bioavailability. Generally, the bioavailability of oral drugs follows the order: solution > suspension > capsule > tablet > coated tablet.
- Rectal The administration of suppositories is usually reserved for situations in which oral administration is difficult. This route is more frequently used in small children. The rectum is devoid of villi, thus absorption is often slow.
B. Parenteral Routes
- Intravenous injection Used when a rapid clinical response is necessary, e.g., an acute asthmatic episode. This route allows one to achieve relatively precise drug concentrations in the plasma, since bioavailability is not a concern. Most drugs should be injected over 1-2 minutes in order to prevent the occurrence of very high drug concentrations in the injected vein, possibly causing adverse effects. Some drugs, particularly those with narrow therapeutic indices or short half-lives, are best administered as a slow IV infusion or drip.
- Intra-arterial injection Used in certain special situations, notably with anticancer drugs, in an effort to deliver a high concentration of drug to a particular tissue. Typically, the injected artery leads directly to the target organ.
- Intrathecal injection The blood-brain barrier limits the entry of many drugs into cerebrospinal fluid. Under some circumstances, usually life-threatening, antibiotics, antifungals and anticancer drugs are given via lumbar puncture and injection into the subarachnoid space.
- Intramuscular injection Drugs may be injected into the arm (deltoid), thigh (vastus lateralis) or buttocks (gluteus maximus). Because of differences in vascularity, the rates of absorption differ, with arm > thigh > buttocks. Drug absorption may be slow and erratic. The volume of injection, osmolality of the solution, lipid solubility and degree of ionization influence absorption. It should not be assumed that the IM route is as reliable as the IV route.
- Subcutaneous injection Some drugs, notably insulin, are routinely administered SC. Drug absorption is generally slower SC than IM, due to poorer vascularity. Absorption can be facilitated by heat, massage or vasodilators. It can be slowed by coadministration of vasoconstrictors, a practice commonly used to prolong the local action of local anesthetics. As above, arm > thigh.
- Inhalation Volatile anesthetics, as well as many drugs which affect pulmonary function, are administered as aerosols. Other obvious examples include nicotine and tetrahydrocannabinol (THC), which are absorbed following inhalation of tobacco or marijuana smoke. The large alveolar area and blood supply lead to rapid absorption into the blood. Drugs administered via this route are not subject to first-pass liver metabolism.
- Topical application a. Eye For desired local effects. b. Intravaginal For infections or contraceptives. c. Intranasal For alleviation of local symptoms. d. Skin Topical drug administration for skin disorders minimizes systemic exposure. However, systemic absorption does occur and varies with the area, site, drug, and state of the skin. Dimethyl sulfoxide (DMSO) enhances the percutaneous absorption of many drugs, but its use is controversial because of concerns about its toxicity. e. Drug patches (drug enters systemic circulation by zero order kinetics – a constant amount of drug enters the circulation per unit time).
B. Physicochemical Factors: pH Partition Theory
- Background review The simplest definition of an acid is that it is a substance, charged or uncharged, that liberates hydrogen ions (H+) in solution. A base is a substance that can bind H+ and remove them from solution. Strong acids, strong bases, as well as strong electrolytes are essentially completely ionized in aqueous solution. Weak acids and weak bases are only partially ionized in aqueous solution and yield a mixture of the undissociated compound and ions.
Thus a weak acid (HA) dissociates reversibly in water to produce hydrogen ion H+ and A-. HA <-----> H+ + A-^ (1)
Applying the mass law equation, which demands that concentrations are in moles per liter, we obtain the following equation: [H+] [A-] = Ka (2) [HA]
where Ka is the ionization or dissociation constant of the acid. Since the ion concentrations are in the numerator, the stronger the acid, the higher the value of Ka. Similarly, one could derive Kb for a weak base BOH. Rearranging equation (2) yields the following: [H+] = Ka [HA] (3) [A-]
Taking the log of both sides of the equation: log [H+] = log Ka + log [HA] - log [A-] (4)
And multiplying by -1, we obtain: -log [H+] = -log Ka - log [HA] + log [A-] (5)
By definition, -log [H+] = pH, and -log Ka = pKa. Thus, we obtain the important relationships for acids: pH = pKa + log [A-] (6) [HA] for bases: pH = pKa + log [B] (7) [BH+]
From the pKa, one can calculate the proportions of drug in the charged and uncharged forms at any pH: log [A-] = (pH - pKa) (8) [HA] [A-] = 10 (pH – pKa) (9) [HA] [B] = 10 (pH-pKb) (10) [BH+] pKb = (1-pKa)
- Ion trapping The influence of pH on transfer of drugs across membranes.
What does this background review have to do with pharmacology. Plenty! Most drugs are too large to pass through membrane channels and must diffuse through the lipid portion of the cell membrane. Nonionized drug molecules are readily lipid-soluble, while ionized molecules are lipophobic and are insoluble.
The distribution of a drug across the cell membrane is usually determined by its pKa and the pHs on both sides of a membrane. The difference of pH across a membrane influences the total concentration of drug on either side, since, by diffusion, at equilibrium the concentration of nonionized drug will be the same on either side.
For example, let's consider the influence of pH on the distribution of a drug which is a weak acid (pKa = 4.4) between plasma (pH = 7.4) and gastric juice (pH = 1.4). The mucosa can be considered to be a simple lipid barrier.
Figure 1
III. DRUG DISTRIBUTION
Once in the blood, drugs are simultaneously distributed throughout the body and eliminated. Typically, distribution is much more rapid than elimination, is accomplished via the circulation, and is influenced by regional blood flow.
A. Compartments
- Central Compartment The central compartment includes the well-perfused organs and tissues (heart, blood, liver, brain and kidney) with which drug equilibrates rapidly.
- Peripheral Compartment(s) The peripheral compartment(s) include(s) those organs (e.g., adipose and skeletal muscle) which are less well-perfused, and with which drug therefore equilibrates more slowly. Redistribution from one compartment to another often alters the duration of effect at the target tissue. For example, thiopental, a highly lipid-soluble drug, induces anesthesia within seconds because of rapid equilibration between blood and brain. Despite the fact that the drug is slowly metabolized, however, the duration of anesthesia is short because of drug redistribution into adipose tissue, which can act as a storage site, or drug reservoir.
- Special Compartments Several special compartments deserve mention. Entry of drug into the cerebrospinal fluid (CSF) and central nervous system (CNS) is restricted by the structure of the capillaries and pericapillary glial cells (the choroid plexus is an exception). The blood-brain barrier limits the success of antibiotics, anticancer drugs and other agents used to treat CNS diseases. Drugs also have relatively poor access to pericardial fluid, bronchial secretions and fluid in the middle ear, thus making the treatment of infections in these regions difficult.
B. Protein Binding
Many drugs bind to plasma proteins. Weak acids and neutral drugs bind particularly to albumin, while basic drugs tend to bind to alpha-1-acid glycoprotein (orosomucoid). Some drugs even bind to red cell surface proteins.
- Effects on drug distribution Only that fraction of the plasma drug concentration which is freely circulating (i.e., unbound) can penetrate cell membranes. Protein binding thus decreases the net transfer of drug across membranes. Drug binding to plasma proteins is generally weak and rapidly reversible, however, so that protein-bound drug can be considered to be in a temporary storage compartment. The protein concentration of extravascular fluids (e.g., CSF, lymph, synovial fluid) is very low. Thus, at equilibrium (when the concentrations of free drug are equal), the total drug concentration in plasma is usually higher than that in extravascular fluid. The extent of protein binding must be considered in interpreting "blood levels" of drugs.
- Effects on drug elimination The effects of plasma protein binding on drug elimination are complex. For drugs excreted only by renal glomerular filtration, protein binding decreases the rate of elimination since only the free drug is filtered. For example, the rates of renal excretion of several tetracyclines are inversely related to their extent of plasma protein binding. Conversely, however, if drug is eliminated by hepatic metabolism or renal tubular secretion, plasma protein binding may promote drug elimination by increasing the rate that that drug is presented for elimination.
- Tissue binding Binding to tissue proteins may cause local concentration of drug. For example, if a drug is bound more extensively at intracellular than at extracellular sites, the intracellular and extracellular concentrations of free drug may be equal or nearly so, but the total intracellular drug concentration may be much greater than the total extracellular concentration.
C. Apparent volume of distribution (AVD or Vd). The volume of distribution, or more properly the apparent volume of distribution, is calculated from measurements of the total concentration of drug in the blood compartment after a single IV injection. Suppose that we injected someone IV with 100 mg of a drug, and measured the blood concentration of the drug repeatedly during the next several hours. We then plot the blood concentrations (on a log scale) against time, and obtain the following graph:
IV. DRUG BIOTRANSFORMATION
The body is exposed to a wide variety of foreign compounds, called xenobiotics. Exposure to some such compounds is unintentional (e.g., environmental or food substances), while others are deliberately used as drugs. The following discussion of drug biotransformation is applicable to all xenobiotics, and to some endogenous compounds (e.g., steroids) as well.
The kidneys are capable of eliminating drugs which are low in molecular weight, or which are polar and fully ionized at physiologic pH. Most drugs do not fit these criteria, but rather are fairly large, unionized or partially ionized, lipophilic molecules. The general goal of drug metabolism is to transform such compounds into more polar (i.e., more readily excretable) water soluble products. For example, were it not for biotransformation to more water-soluble products, thiopental, a short-acting, lipophilic anesthetic, would have a half-life of more than 100 years! Imagine, without biotransformation reactions, anesthesiologists might grow old waiting for patients to wake up.
Most products of drug metabolism are less active than the parent compound. In some cases, however, metabolites may be responsible for toxic, mutagenic, teratogenic or carcinogenic effects. For example, overdoses of acetaminophen owe their hepatotoxicity to a minor metabolite which reacts with liver proteins. In some cases, with metabolism of so-called prodrugs, metabolites are actually the active therapeutic compounds. The best example of a prodrug is cyclophosphamide, an inert compound which is metabolized by the liver into a highly active anticancer drug.
A. Sites of drug metabolism
- At the organ level The liver is the primary organ of drug metabolism. The gastrointestinal tract is the most important extrahepatic site. Some orally administered drugs (e.g., isoproterenol) are conjugated extensively in the intestinal epithelium, resulting in decreased bioavailability. The lung, kidney, intestine, skin and placenta can also carry out drug metabolizing reactions. Because of its enormous perfusion rate and its anatomic location with regard to the circulatory system, the lungs may exert a first-pass effect for drugs administered IV.
- At the cellular level Most enzymes involved in drug metabolism are located within the lipophilic membranes of the smooth endoplasmic reticulum (SER). When the SER is isolated in the laboratory by tissue homogenation and centrifugation, the SER membranes re-form into vesicles called microsomes. Since most of the enzymes carry out oxidation reactions, this SER complex is referred to as the microsomal mixed function oxidase (MFO) system.
- At the biochemical level Phase I reactions refer to those which convert a drug to a more polar compound by introducing or unmasking polar functional groups such as - OH, -NH 2 , or -SH. Some Phase I products are still not eliminated rapidly, and hence undergo Phase II reactions involving conjugation of the newly established polar group with endogenous compounds such as glucuronic acid, sulfuric acid, acetic acid, or amino acids (typically glycine). Glucuronide formation is the most common phase II reaction. Sometimes,
the parent drug may undergo phase II conjugation directly. In some cases, a drug may undergo a series of consecutive reactions resulting in the formation of dozens of metabolites. Most phase I MFO biotransformation reactions are oxidative in nature and require a reducing agent (NADPH), molecular oxygen, and a complex of microsomal enzymes; the terminal oxidizing enzyme is called cytochrome P 450 , a hemoprotein so named because its carbon monoxide derivative absorbs light at 450 nm. We now know that cytochrome P 450 is actually a family of enzymes which differ primarily with regard to their substrate specificities. Advances in molecular biology have led to the identification of more than 70 distinct P 450 genes in various species. The nomenclature of the P 450 reductase gene products has become complex. Based upon their amino acid homologies, the P 450 reductases have been grouped into families such that a cytochrome P 450 from one family exhibits < 40% amino acid sequence identity to a cytochrome P 450 in another gene family. Several of the gene families are further divided into subfamilies, denoted by letters A, B, C, etc. Eight major mammalian gene families have been defined (see Table 1).
Table 1: Major Cytochrome P450 Gene Families
P 450 Gene Family/Subfamily
Characteristic Substrates
Characteristic Inducers
Characteristic Inhibitor
CYP 1A2 Acetominophen Estradiol Caffeine
Tobacco Char-Grilled Meats Insulin
Cimetidine Amiodarone Ticlopidine
CYP 2C19 Diazepam, Omeprazole Progesterone
Prednisone Rifampin
Cimetidine Ketoconazole Omeprazole
CYP 2C9 Tamoxifen Ibuprofen Fluoxetine
Rifampin Secobarbital
Fluvastatin Lovastatin Isoniazid
CYP 2D6 Debrisoquine Ondansetron Amphetamine
Dexamethasone? Rifampin?
Cimetidine Fluoxetine Methadone
CYP 2E1 Ethanol Benzene Halothane
Ethanol Isoniazid
Disulfiram Water Cress
CYP 3A4, 5, 7 Cyclosporin Clarithromycin Hydrocortisone Vincristine Many, many others
Barbiturates Glucocorticoids Carbamazepine St. John’s Wort
Cimetidine Clarithromycin Ketoconazole Grapefruit Juice Many others
Table 2: Drug Biotransformation Reactions (Goodman & Gilman, 7th edition, pp. 16-17)
Figure 4
(Goodman & Gilman, 8th edition, p. 16.)
V. DRUG ELIMINATION
The kidney is the most important organ for the excretion of drugs and/or their metabolites. Some compounds are also excreted via bile, sweat, saliva, exhaled air, or milk, the latter a possible source of unwanted exposure in nursing infants. Drug excretion may involve one or more of the following processes.
A. Renal Glomerular Filtration Glomeruli permit the passage of most drug molecules, but restrict the passage of protein-bound drugs. Changes in glomerular filtration rate affect the rate of elimination of drugs which are primarily eliminated by filtration (e.g., digoxin, kanamycin).
B. Renal Tubular Secretion The kidney can actively transport some drugs (e.g., dicloxacillin) against a concentration gradient, even if the drugs are protein-bound. (Actually, only free drug is transported, but the protein-drug complex rapidly dissociates.) A drug called probenecid competitively inhibits the tubular secretion of the penicillins, and may be used clinically to prolong the duration of effect of the penicillins.
C. Renal Tubular Reabsorption Many drugs are passively reabsorbed in the distal renal tubules. Reabsorption is influenced by the same physicochemical factors that influence gastrointestinal absorption: nonionized, lipid-soluble drugs are extensively reabsorbed into
Figure 5
Figure 5 shows the change in plasma drug concentration [D]p with time after administration of a single oral dose. The interrupted horizontal lines show the minimum effective concentration (MEC) and toxic concentration (TC). A therapeutic effect can be expected only when plasma level is above the MEC and below the TC.
Since effect usually is proportional to plasma (or tissue) concentration, the objective of therapy is to attain and maintain the needed plasma concentration for the period needed, whether this is days or years. To do this, one need understand something about pharmacokinetics.
Most of the pharmacokinetic concepts we will deal with describe the behavior of a simple one-compartment model in which drug equilibrates so rapidly in the entire volume that the dominant factors are the rates of absorption (input) and elimination (output).
Figure 6
In this model kin describes the rate of input and kout the rate of output. When these rates are equal, the amount and concentration in the compartment are constant.
Figure 7
Models of drug distribution and elimination. The effect of adding drug to the blood by rapid intravenous injection is represented by expelling a known amount of the agent into a beaker. The time course of the amount of drug in the beaker is shown in the graphs at the right. In the first example (A), there is no movement of drug out of the beaker, so the graph shows only a steep rise to maximum followed by a plateau. In the second example (B), a route of elimination is presented and the graph shows a slow decay after a sharp rise to a maximum. Because the level of material in the beaker falls, the "pressure" driving the elimination process also falls, and the slope of the curve decreases, approaching the steady state asymptotically. This is an exponential decay curve. In the third model (C), drug placed in the first compartment (blood) equilibrates rapidly with the second compartment (extravascular volume) and the amount of drug in "blood" declines logarithmically to a new steady state. The fourth model (D), illustrates a more realistic combination of elimination mechanism and extravascular equilibration. The resulting graph shows an early distribution phase followed by the slower elimination phase. These curves can be linearized by plotting the logarithm of the amount of drug against time.
- Zero order kinetics Zero order kinetics describe processes in which a constant amount of drug is absorbed or eliminated per unit time. A constant rate intravenous infusion is one example of a zero order process.
For most drugs, absorption and elimination follow first order kinetics because the drug concentration is not sufficient to saturate the mechanism for absorption or elimination. If the process saturates, then zero order kinetics apply. For some drugs, elimination kinetics are dose-dependent (or more correctly, concentration- dependent). As the plasma level increases, the value of t1/2e increases; the plasma concentration increases disproportionately with increases in dose, and finally, elimination rate becomes independent of plasma concentration.
C. The time course of change in plasma concentration When a drug is administered in a single dose, and when absorption and elimination are first order processes, it is reasonable to have some idea of the effects of three variables (t1/2a, dose and t (^) 1/2e) on the time-course of change in plasma concentration, as shown in Figure 9.
- More rapid absorption will increase the peak plasma concentration, decrease the latency (time required to attain drug effect) and decrease the duration of effect.
- An increase in dose will also decrease latency and increase peak plasma concentration and increase duration of effect.
- More rapid elimination will decrease peak plasma concentration and duration of effect.
Figure 9
D. The Plateau Effect When repeated doses of a drug are given at sufficiently short intervals, and elimination is a first order process, the plasma concentration (and total body store) will increase to a steady value or plateau. The same thing will happen if a drug is administered as a constant rate intravenous infusion (zero order in) and eliminated by a first order process. The latter case may be simpler to consider first.
During constant IV infusion, the total body store increases exponentially to a steady value. The half-time for the change in plasma concentration is equal to t (^) 1/2e. This means that 50% of the final concentration is attained in one t (^) 1/2e, 75% in two and 87.5% in three. 90% of the final value is attained in 3.3t1/2e; this is a useful fact to remember.
With intermittent dosing, unless the dose interval is quite long compared to t1/2e, accumulation and the increase in plasma concentration will follow a similar time- course, but there will be fluctuations in plasma level between doses. The shorter the dose interval and the smaller the dose, the smaller will be the fluctuations.
Figure 10
