Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs PDF

Pharmacokinetics: Membrane Chapter 2 Transport, Absorption and Distribution of Drugs Pharmacokinetics is the quantitative study of drug All pharmacokinetic processes involve trans­ movement in, through and out of the body. The port of the...

Pharmacokinetics: Membrane Chapter 2 Transport, Absorption and Distribution of Drugs Pharmacokinetics is the quantitative study of drug All pharmacokinetic processes involve trans­ movement in, through and out of the body. The port of the drug across biological membranes. overall scheme of pharmacokinetic processes is Biological membrane This is a bilayer (about depicted in Fig. 2.1. The intensity of response 100 Å thick) of phospholipid and cholesterol is related to concentration of the drug at the site mole­cules, the polar groups (glyceryl phosphate of action, which in turn is dependent on its attached to ethanolamine/choline or hydroxyl pharmacokinetic properties. Pharmacokinetic group of cholesterol) of these are oriented at the considerations, therefore, deter­mine the route(s) two surfaces and the nonpolar hydrocarbon chains of administration, dose, latency of onset, time are embedded in the matrix to form a continu­ of peak action, duration of action and frequency ous sheet. This imparts high electrical resistance of adminis­tration of a drug. and relative impermeability to the membrane. Fig. 2.1: Schematic depiction of pharmacokinetic processes  16 GENERAL PHARMACOLOGY Fig. 2.2: Illustration of the organisation of biological membrane Fig. 2.3: Illustration of passive diffusion and filtration Extrinsic and intrinsic protein molecules are across the lipoidal biological membrane with aqueous adsorbed on the lipid bilayer (Fig. 2.2). Glyco­ pores proteins or glycolipids are formed on the surface SECTION 1 by attachment to polymeric sugars, aminosugars or sialic acids. The specific lipid and protein Lipid soluble drugs diffuse by dissolving compo­sition of different membranes differs in the lipoidal matrix of the membrane (Fig. according to the cell or the organelle type. 2.3), the rate of transport being proportional The proteins are able to freely float through to the lipid : water partition coefficient of the the membrane: associate and organize or vice drug. A more lipid-soluble drug attains higher versa. Some of the intrinsic ones, which extend concentra­tion in the membrane and diffuses through the full thickness of the mem­ brane, quickly. Also, greater the difference in the surround fine aqueous pores. Paracellular spaces concentration of the drug on the two sides of or channels also exist between certain epithelial/ the membrane, faster is its diffusion. endothelial cells. Other adsorbed proteins have Influence of pH Most drugs are weak enzymatic, carrier, receptor or signal transduction electro­l ytes, i.e. their ionization is pH properties. Lipid molecules also are capable of dependent (contrast strong electrolytes that are lateral move­ment. Thus, biological membranes nearly completely ionized at acidic as well as are highly dynamic structures. alkaline pH). The ionization of a weak acid Drugs are transported across the membranes by: HA is given by the equation: (a) Passive diffusion and filtration [A¯ ] (b) Specialized transport pH = pKa + log —–—...(1) [HA] Passive diffusion pKa is the negative logarithm of acidic disso­ The drug diffuses across the membrane in the ciation constant of the weak electrolyte. If the direction of its concentration gradient (high concentra­tion of ionized drug [A¯ ] is equal to low), the membrane playing no active role to concentration of unionized drug [HA], then in the process. This is the most important  [A¯ ] mechanism for majority of drugs; drugs are —–— = 1 foreign substances (xenobiotics), and special­   [HA] ized mechanisms are developed by the body since log 1 is 0, under this condition primarily for normal metabolites. pH = pKa...(2)  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 17 Thus, pKa is numerically equal to the pH at (pH 7.0) and then only slowly passes to the which the drug is 50% ionized. extracellular fluid. This is called ion trapping, If pH is increased by 1 scale, then— i.e. a weak electrolyte crossing a membrane to encounter a pH from which it is not able to log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10 escape easily. This may contribute to gastric Similarly, if pH is reduced by 1 scale, then— mucosal cell damage caused by aspirin. [A¯ ]/[HA] = 1/10 (c) Basic drugs attain higher concentration intracellularly (pH 7.0 vs 7.4 of plasma). Thus, weakly acidic drugs, which form salts (d) Acidic drugs are ionized more in alkaline with cations, e.g. sod. phenobarbitone, sod. sul­ urine—do not back diffuse in the kidney fadiazine, pot. penicillin-V, etc. ionize more at tubules and are excreted faster. Accordingly, basic alkaline pH and 1 scale change in pH causes 10 drugs are excreted faster if urine is acidified. fold change in ionization. Lipid-soluble nonelectrolytes (e.g. ethanol, Weakly basic drugs, which form salts with diethyl-ether) readily cross biological membranes anions, e.g. atropine sulfate, ephedrine HCl, and their transport is pH independent. chloro­­quine phosphate, etc. conversely ionize more at acidic pH. Ions being lipid insoluble, Filtration do not diffuse and a pH difference across a Filtration is passage of drugs through aqueous CHAPTER 2 membrane can cause differential distribution of pores in the membrane or through paracellular weakly acidic and weakly basic drugs on the spaces. This can be accelerated if hydrodynamic two sides (Fig. 2.4). flow of the solvent is occurring under hydrostatic or osmotic pressure gradient, e.g. across most capillaries including glomeruli. Lipid-insoluble drugs cross biological membranes by filtration if their mole­ c ular size is smaller than the diameter of the pores (Fig. 2.3). Majority of cells (intestinal mucosa, RBC, etc.) have very small pores (4 Å) and drugs with MW > 100 or 200 are not able to penetrate. However, capillaries (except those in brain) have large paracellular spaces (40 Å) and most drugs (even albumin) can filter through these (Fig. 2.8). As such, diffusion of drugs across capillaries is Fig. 2.4: Influence of pH difference on two sides of a dependent on rate of blood flow through them biological membrane on the steady-state distribution of rather than on lipid solubility of the drug or a weakly acidic drug with pKa = 6 pH of the medium. Implications of this consideration are: (a) Acidic drugs, e.g. aspirin (pKa 3.5) are Specialized transport largely unionized at acid gastric pH and are This can be carrier mediated or by vesicular absorbed from stomach, while bases, e.g. transport (endocytosis, exocytosis). atropine (pKa 10) are largely ionized and are absorbed only when they reach the intestines. Carrier transport (b) The unionized form of acidic drugs which All cell membranes express a host of transmem­ crosses the surface membrane of gastric mucosal brane proteins which serve as carriers or cell, reverts to the ionized form within the cell transporters for physiologically important ions,  18 GENERAL PHARMACOLOGY SECTION 1 Fig. 2.5: Illustration of different types of carrier mediated transport across biological membrane ABC—ATP-binding cassette transporter; SLC—Solute carrier transporter; M—Membrane A. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient (high to low) and does not require energy B. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrate against its concentration gradient (low to high) C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhill movement of another substrate ‘B’ in the same direction D. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhill movement of another substrate ‘B’ in the opposite direction nutrients, metabolites, transmitters, etc. across through channels. Depending on requirement the membrane. At some sites, certain transport­ of energy, carrier transport is of two types: ers also translocate xenobiotics, including drugs a. Facilitated diffusion The transporter, and their metabolites. In contrast to channels, belonging to the super-family of solute carrier which open for a finite time and allow pas­ (SLC) transporters, operates passively without sage of specific ions, transporters combine needing energy and translocates the substrate transiently with their substrate (ion or organic in the direction of its electrochemical gradi­ compound)—undergo a conformational change ent, i.e. from higher to lower concentration carrying the substrate to the other side of the (Fig. 2.5A). It merely facilitates permeation membrane where the substrate dissociates and of a poorly diffusible substrate, e.g. the entry the transporter returns back to its original of glucose into muscle and fat cells by the state (Fig. 2.5). Carrier transport is specific glucose transporter GLUT 4. for the substrate (or the type of substrate, b. Active transport It requires energy, is e.g. an organic anion), saturable, competitively inhibited by metabolic poisons, and transports the inhibited by analogues which utilize the same solute against its electrochemical gradient (low to transporter, and is much slower than the flux high), resulting in selective accumulation of the  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 19 substance on one side of the membrane. Drugs The organic anion transporting polypeptide (OATP) related to normal metabolites can utilize the and organic cation transporter (OCT), highly expressed in liver canaliculi and renal tubules, are secondary active transport processes meant for these, e.g. levodopa transporters important in the metabolism and excretion and methyl dopa are actively absorbed from the of drugs and metabolites (especially glucuronides). The gut by the aromatic amino acid transporter. In Na+,Cl– dependent neurotransmitter transporters for norepi­ addition, the body has developed some relatively nephrine, serotonin and dopamine (NET, SERT and DAT) nonselective transporters, like P-glycoprotein are active SLC transporters that are targets for action of drugs like tricyclic antidepressants, selective serotonin (P-gp), to deal with xenobiotics. Active transport reuptake inhibitors (SSRIs), cocaine, etc. Similarly, the can be primary or secondary depending on the Vesicular monoamine transporter (VMAT-2) of adrenergic source of the driving force. and serotonergic storage vesicles transports catecholamines and 5-HT into the vesicles by exchanging with H+ions, i. Primary active transport Energy is and is inhibited by reserpine. The absorption of glucose obtained directly by the hydrolysis of ATP (Fig. in intestines and renal tubules is through secondary 2.5B). The transporters belong to the superfamily active transport by sodium-glucose transporters (SGLT1 of ATP binding cassettee (ABC) transporters and SGLT2). whose intra­cellular loops have ATPase activity. As indicated earlier, carrier transport (both They mediate only efflux of the solute from facilitated diffusion and active transport) is the cytoplasm, either to extracellular fluid or saturable and follows the Michaelis-Menten into an intracellular organelli (endoplasmic kinetics. The maximal rate of transport is CHAPTER 2 reticulum, mitochondria, etc.) dependent on the density of the transporter Encoded by the multidrug resistance 1 (MDR1) gene, P-gp is the most well known primary active transporter in a particular membrane, and its rate con­ expressed in the intestinal mucosa, renal tubules, bile stant (Km), i.e. the substrate concentration canaliculi, choroidal epithelium, astrocyte foot processes at which rate of transport is half maximal, around brain capillaries (the blood-brain barrier), testicular is governed by its affinity for the substrate. and placental microvessels, which pumps out many drugs/ metabolites and thus limits their intestinal absorp­ tion, Genetic polymorphism can alter both the penetration into brain, testes and foetal tissues as well as density and affinity of the transporter pro­ promotes biliary and renal elimination. Many xenobiotics tein for different substrates and thus affect which induce or inhibit P-gp also have a similar effect on the drug metabolizing isoenzyme CYP3A4, indicating the pharmacokinetics of drugs. Moreover, their synergistic role in detoxification of xenobiotics. tissue specific drug distribution can occur Other primary active transporters of pharmacological due to the presence of specific transporters significance are multidrug resistance associated protein 2 in certain cells. (MRP 2) and breast cancer resistance protein (BCRP). ii. Secondary active transport In this type of Vesicular transport (endocytosis, active transport effected by another set of SLC exocytosis) transporters, the energy to pump one solute is derived from the downhill movement of another Certain substances with very large or imperme­ solute (mostly Na+). When the concentration able molecules are transported inside the cell gradients are such that both the solutes move (endocytosis) or extruded from it (exocytosis) in the same direction (Fig. 2.5C), it is called by enclosing their particles into tiny vesicles. symport or cotransport, but when they move A binding protein located on the membrane in opposite directions (Fig. 2.5D), it is termed complexes with the substance and initiates antiport or exchange transport. Metabolic energy vesicle formation (Fig. 2.6). The vesicle then (from hydrolysis of ATP) is spent in maintain­ detaches from the membrane and may remain ing high transmembrane electrochemical gradient stored within the cell, or it may release the of the second solute (generally Na+). The SLC substance in the cytoplasm, or it may move to transporters mediate both uptake and efflux of the opposite membrane fuse with it to release drugs and metabolites. the substance across the cell (exocytosis).  20 GENERAL PHARMACOLOGY SECTION 1 Fig. 2.6: Illustration of vesicular transport (endocytosis and exocytosis). Endocytosis: The large molecular particle (P) binds to a binding protein (B) on the surface of the cell. The membrane invaginates to form a vesicle which nicks off, and the vesicle may remain stored within the cell, or it may disintegrate to release the substance in the cytoplasm, or be extruded across the cell by exocytosis. Exocytosis: The particle or the transmitter/hormone(T/H) stored within intracellular vesicles, generally as a complex with a storage protein (S), is secreted by exocytosis. On activation the vesicle translocates to and fuses with the membrane. All contents of the vesicle are then poured out in the extracellular space. Vesicular transport is applicable to proteins ABSORPTION and other big mole­cules, and contributes little to transport of most drugs, barring few like vit B12 Absorption is movement of the drug from its which is absorbed from the gut after binding to site of administration into the circulation. Not intrinsic factor (a protein). Most hormones (insulin, only the fraction of the administered dose that etc.) and neurotransmitters, like noradrenaline, are secreted/released from the cell/nerve ending by gets absor­bed, but also the rate of absorption exocytosis. Activation of the secretory cell/nerve is important. Except when given i.v., the drug ending prompts fusion of the storage vesicle to has to cross biological membranes; absorption the surface membrane followed by extrusion of is governed by the above described principles. its contents into the extracellular space. Other factors affecting absorption are:  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 21 Aqueous solubility Drugs given in solid form of the drug in solid dosage form governs rate must dissolve in the aqueous biophase before of dissolution and in turn rate of absorption. they are absorbed. For poorly water soluble Presence of food dilutes the drug and retards drugs (aspirin, griseofulvin) rate of dissolution absorption. Further, certain drugs form poorly governs rate of absorption. Ketoconazole dis­ absorbed complexes with food constituents, solves at low pH: gastric acid is needed for its e.g. tetracyclines with calcium present in absorption. Obviously, a drug given as watery milk; moreover food delays gastric emptying. solution is absorbed faster than when the same Thus, most drugs are absorbed better if taken is given in solid form or as oily solution. in empty stomach. However, there are some Concentration Passive diffusion depends on exceptions, e.g. fatty food greatly enhances con­­centration gradient; drug given as concen­ lumefantrine absorption. Highly ionized drugs, trated solution is absorbed faster than from e.g. gentamicin, neostig­mine are poorly absorbed dilute solution. when given orally. Certain drugs are degraded in the gastrointes­ Area of absorbing surface Larger is the tinal tract, e.g. penicillin G by acid, insulin by surface area, faster is the absorption. peptidases, and are ineffective orally. Enteric Vascularity of the absorbing surface Blood coated tablets (having acid resistant coating) circu­­ lation removes the drug from the site of and sustained release preparations (drug particles CHAPTER 2 absorption and maintains the concentration coated with slowly dissolving material) can be gradient across the absorbing surface. Increased used to over­come acid lability, gastric irritancy blood flow hastens drug absorption just as wind and brief duration of action. hastens drying of clothes. The oral absorption of certain drugs is Route of administration This affects drug low because a fraction of the absorbed drug absorp­­­tion, because each route has its own is extru­d ed back into the intestinal lumen peculiarities. by the efflux transporter P-gp located in the gut epithelium. The low oral bioavail­ Oral ability of digoxin and cyclo­ sporine is partly The effective barrier to orally administered drugs accounted by this mechanism. Inhibitors of P-gp is the epithelial lining of the gastrointestinal like quinidine, verapamil, erythromycin, etc. tract, which is lipoidal. Nonionized lipid soluble enhance, while P-gp inducers like rifampin and drugs, e.g. ethanol are readily absorbed from phenobarbitone reduce the oral bioavailability stomach as well as intestine at rates propor­ of these drugs. tional to their lipid : water partition coefficient. Absorption of a drug can be affected by other Acidic drugs, e.g. salicylates, barbiturates, etc. concurrently ingested drugs. This may be a lumi- are predominantly unionized in the acid gastric nal effect: formation of insoluble complexes, e.g. juice and are absorbed from stomach, while basic tetracyclines and iron preparations with calcium drugs, e.g. morphine, quinine, etc. are largely salts and antacids, phenytoin with sucralfate. Such ionized and are absorbed only on reaching the interaction can be mini­mized by administering the duodenum. However, even for acidic drugs two drugs at 2–3 hr intervals. Alteration of gut absorption from stomach is slower, because flora by antibiotics may disrupt the enterohepatic the mucosa is thick, covered with mucus and cycling of oral contraceptives and digoxin. Drugs the surface area is small. Absorbing surface can also alter absorption by gut wall effects: altering area is much larger in the small intestine due motility (anti­cholinergics, tri­cyclic antidepressants, to villi. Thus, faster gastric emptying acceler­ opioids retard motility while metoclopramide ates drug absorption in general. Dissolution is enhances it) or causing mucosal damage (neomycin, a surface phenomenon, therefore, particle size methotrexate, vinblastine).  22 GENERAL PHARMACOLOGY Subcutaneous and Intramuscular get absorbed through the nasolacrimal duct, By these routes the drug is deposited directly e.g. timolol eye drops can produce bradycardia in the vicinity of the capillaries. Lipid soluble and precipitate asthma. Mucous membranes of drugs pass readily across the whole surface mouth, rectum, vagina absorb lipophilic drugs: of the capillary endothelium. Capillaries hav­ estrogen cream applied vaginally has produced ing large paracellular spaces do not obstruct gynaeco­mastia in the male partner. absorption of even large lipid insoluble molecules Bioavailability or ions (Fig. 2.9A). Very large molecules are absorbed through lympha­tics. Thus, many drugs Bioavailability refers to the rate and extent not absorbed orally are absorbed paren­ terally. of absorption of a drug from a dosage form Absorption from s.c. site is slower than that administered by any route, as determined by from i.m. site, but both are generally faster its concentration-time curve in blood or by its and more consistent/ predictable than oral excretion in urine (Fig. 2.7). It is a measure absorption. Application of heat and muscular of the fraction (F ) of administered dose of a exercise accelerate drug absorption by increasing drug that reaches the systemic circulation in blood flow, while vasoconstrictors, e.g. adrena­ the unchanged form. Bioavailability of drug injected i.v. is 100%, but is frequently lower line injected with the drug (local anaes­ thetic) after oral ingestion because— retard absorp­tion. Incorporation of hyalu­ro­nidase SECTION 1 (a) the drug may be incompletely absorbed. facilitates drug absorption from s.c. injection (b) the absorbed drug may undergo first pass by promoting spread. Many depot pre­p ara­ metabolism in the intestinal wall/liver or be tions, e.g. benzathine penicillin, protamine zinc excreted in bile. insulin, depot proges­tins, etc. can be given by these routes. Topical sites (skin, cornea, mucous membranes) Systemic absorption after topical application depends primarily on lipid solubility of drugs. However, only few drugs significantly penetrate intact skin. Hyoscine, fentanyl, GTN, nicotine, testosterone, and estradiol (see p. 12) have been used in this manner. Corticosteroids applied over extensive areas of skin can produce sys­ temic effects and pituitary-adrenal suppression. Absorption can be promo­ted by rubbing the drug incorporated in an olegenous base or by use of occlusive dressing which increases hydration of the skin. Organo­phosphate insecti­cides com­ Fig. 2.7: Plasma concentration-time curves depicting bioavailability differences between three formulations of ing in contact with skin can produce systemic a drug containing the same amount toxicity. Abraded surfaces readily absorb drugs, Note that formulation B is more slowly absorbed than e.g. tannic acid applied over burnt skin has A, and though ultimately both are absorbed to the same produced hepatic necrosis. extent (area under the curve same), B may not produce therapeutic effect after a single dose; however average Cornea is permeable to lipid soluble, unioni­ blood levels may be similar with both A and B formulations zed physostigmine but not to highly ionized when repeated doses are given; C is absorbed to a lesser neostig­mine. Drugs applied as eye drops may extent—resulting in lower bioavailability  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 23 Incomplete bioavailability after s.c. or i.m. product or to another brand of the same drug injection is less common, but may occur due have often been exaggerated. to local binding of the drug. Bioequivalence Oral formulations of a drug DISTRIBUTION from different manufacturers or different batches Once a drug has gained access to the blood from the same manufacturer may have the same stream, it gets distributed to other tissues that amount of the drug (chemically equivalent) but initially had no drug, concentration gradient may not yield the same blood levels—biologi- being in the direction of plasma to tissues. cally inequivalent. Two preparations of a drug The extent of distribution of a drug and its are considered bioequivalent when the rate and pattern of tissue distribution depends on its: extent of bioavai­lability of the active drug lipid solubility from them is not significantly different under ionization at physiological pH (a function suitable test conditions. of its pKa) Before a drug administe­red orally in solid extent of binding to plasma and tissue proteins dosage form can be absorbed, it must break into presence of tissue-specific transporters individual particles of the active drug (disinte­ differences in regional blood flow. gra­tion). Tablets and capsules contain a number Movement of drug proceeds until an equilibrium of other materials—diluents, stabilizing agents, CHAPTER 2 is established between unbound drug in the binders, lubricants, etc. The nature of these plasma and the tissue fluids. Subsequently, there as well as details of the manu­facture process, is a parallel decline in both due to elimination. e.g. force used in compressing the tablet, may affect disintegration. The released drug must Apparent volume of distribution (V) Presuming then dissolve in the aqueous gastro­intestinal that the body behaves as a single homogeneous contents. The rate of dissolution is governed compartment with volume V into which the by the inherent solubility, particle size, crystal drug gets immediately and uniformly distributed form and other physical properties of the drug. dose administered i.v. Differences in bioavailability may arise due to V = —————————...(3) plasma concentration variations in disintegration and dissolution rates. Differences in bioavailability are seen mostly Since in the example shown in Fig. 2.8, the with poorly soluble and slowly absorbed drugs. drug does not actually distribute into 20 L of Reduction in particle size increases the rate of body water, with the exclusion of the rest of absorption of aspirin (microfine tablets). The it, this is only an apparent volume of distri­ amount of griseofulvin and spironolactone in bution which can be defined as “the volume the tablet can be reduced to half if the drug that would accommodate all the drug in the particle is microfined. There is no need to body, if the concentration throughout was the reduce the particle size of freely water soluble same as in plasma”. Thus, it describes amount drugs, e.g. paracetamol. of the drug present in the body as a multiple Bioavailability variation assumes practical of that con­tained in a unit volume of plasma. significance for drugs with low safety margin Considered together with drug clearance, this (digoxin) or where dosage needs precise control is a very useful pharmacokinetic concept. (oral hypoglycaemics, oral anticoagulants). It Lipid-insoluble drugs do not enter cells— may also be responsible for success or failure V approximates extracellular fluid volume, e.g. of an antimicrobial regimen. streptomycin, gentamicin 0.25 L/kg. However, in the case of a large number of Distribution is not only a matter of dilu­ drugs bio­availability differences are negligible and tion, but also binding and sequestration. Drugs the risks of changing from branded to generic extensively bound to plasma proteins are largely  24 GENERAL PHARMACOLOGY Factors governing volume of drug distribution Lipid: water partition coefficient of the drug pKa value of the drug Degree of plasma protein binding Affinity for different tissues Fat: lean body mass ratio, which can vary with age, sex, obesity, etc. Diseases like CHF, uremia, cirrhosis drug—plasma concentration falls and the drug is withdrawn from the highly perfused sites. If the site of action of the drug was in one of the highly Fig. 2.8: Illustration of the concept of apparent volume of distribution (V) per­fused organs, redistribution results in termina­ In this example, 1000 mg of drug injected i.v. produces tion of drug action. Greater the lipid solubility steady-state plasma concentration of 50 mg/L, apparent of the drug, faster is its redistribution. Anaes­ volume of distribution is 20 L thetic action of thiopentone sod. injected i.v. is terminated in few minutes due to redistribution. SECTION 1 A relatively short hypnotic action lasting 6–8 restricted to the vascular compartment and have hours is exerted by oral diazepam or nitrazepam low values of V, e.g. diclofenac and warfarin due to redistribution despite their elimination (99% bound) V = 0.15 L/kg. t½ of > 30 hr. However, when the same drug A large value of V indicates that larger quan­ is given repeatedly or continuously over long tity of drug is present in extravascular tissue. periods, the low perfusion high capacity sites Drugs sequestrated in other tissues may have, V get progres­sively filled up and the drug becomes much more than total body water or even body longer acting. mass, e.g. digoxin 6 L/kg, propranolol 4 L/kg, Penetration into brain and CSF The capil­ morphine 3.5 L/kg, because most of the drug lary endothelial cells in brain have tight junctions is present in other tissues, and plasma concen­ and lack large paracellular spaces. Further, an tration is low. Therefore, in case of poisoning, invest­ment of neural tissue (Fig. 2.9B) covers drugs with large volumes of distribution are the capillaries. Together they constitute the so not easily removed by haemodialysis. called blood-brain barrier (BBB). A similar blood- Pathological states, e.g. congestive heart CSF barrier is located in the choroid plexus: failure, uraemia, cirrhosis of liver, etc. can alter capillaries are lined by choroidal epithelium the V of many drugs by altering distribution of having tight junctions. Both these barriers are body water, permeability of membranes, binding lipoidal and limit the entry of nonlipid-soluble proteins or by accumulation of metabolites that drugs, e.g. streptomycin, neostigmine, etc. Only displace the drug from binding sites. lipid-soluble drugs, therefore, are able to pen­ More precise multiple compartment models etrate and have action on the central nervous for drug distribution have been worked out, but system. In addition, efflux transporters like the single compartment model, described above, P-gp and anion transporter (OATP) present in is simple and fairly accurate for many drugs. brain and choroidal vessels extrude many drugs Redistribution Highly lipid-soluble drugs get that enter brain by other processes and serve to initially distributed to organs with high blood flow, augment the protective barrier against potentially i.e. brain, heart, kidney, etc. Later, less vascular harmful xenobiotics. Dopamine does not enter but more bulky tissues (muscle, fat) take up the brain but its precursor levodopa does; as such,  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 25 Fig. 2.9: Passage of drugs across capillaries A. Usual capillary with large paracellular spaces through which even large lipid-insoluble molecules diffuse B. Capillary constituting blood brain or blood-CSF barrier. Tight junctions between capillary endothelial cells and investment of glial processes or choroidal epithelium do not allow passage of nonlipid-soluble molecules/ions CHAPTER 2 the latter is used in parkinsonism. Inflammation limit foetal exposure to maternally administered of meninges or brain increases permeability of drugs. Placenta is a site for drug metabolism these barriers. It has been proposed that some as well, which may lower/modify exposure of drugs accumulate in the brain by utilizing the the foetus to the administered drug. However, transporters for endogenous substances. restricted amounts of nonlipid-soluble drugs, There is also an enzymatic BBB: Monoamine when present in high concent­ration or for long oxidase (MAO), cholines­terase and some other periods in maternal circulation, gain access to enzymes are present in the capillary walls or the foetus. Some influx transporters also operate in the cells lining them. They do not allow at the placenta. Thus, it is an incomplete barrier catecholamines, 5-HT, acetylcholine, etc. to and almost any drug taken by the mother can enter brain in the active form. affect the foetus or the newborn (drug taken The BBB is deficient at the CTZ in the just before delivery, e.g. morphine). medulla oblongata (even lipid-insoluble drugs are emetic) and at certain periventricular sites— Plasma protein binding (anterior hypothalamus). Most drugs possess physicochemical affinity Exit of drugs from the CSF and brain, for plasma proteins and get reversibly bound however, is not dependent on lipid-solubility to these. Acidic drugs generally bind to plasma and is rather unrestricted. This is due to bulk albumin and basic drugs to α1 acid glycoprotein. flow of CSF (alongwith the drug dissolved in Binding to albumin (which is more abundant) is it) back into blood through the arach­noid villi. quantitatively more important. Extent of bind­ Further, non­specific organic anion and cation ing depends on the individual compound; no transport processes (similar to those in renal gene­ralization for a pharmaco­logical or chemi­ tubule) operate at the choroid plexus. cal class can be made (even small chemical Passage across placenta Placental membra­ change can markedly alter protein binding), nes are lipoidal and allow free passage of for example the binding percentage of some lipo­philic drugs, while restricting hydrophilic benzo­diazepines is: drugs. The placental efflux P-gp and other Flurazepam 10% Alprazolam 70% transporters like BCRP, MRP3 also serve to Lorazepam 90% Diazepam 99%  26 GENERAL PHARMACOLOGY Increasing concentrations of the drug can pro­ The same is true of active transport of highly gressively saturate the binding sites: fractional extracted drugs in liver. Plasma protein binding binding may be lower when large amounts of the in this situation acts as a carrier mechanism drug are given. The generally expressed per­cen­ and hastens drug elimination, e.g. excretion of tage binding refers to the usual therapeutic plasma penicillin (elimination t½ is 30 min); metabo­ concentrations of a drug. The clinically significant lism of lidocaine. Highly protein bound drugs implications of plasma protein binding are: are not removed by haemodialysis and need (i) Highly plasma protein bound drugs are special techniques for treatment of poisoning. largely restricted to the vascular compartment (iv) The generally expressed plasma concentra­ because protein bound drug does not cross tions of the drug refer to bound as well as membranes (except through large paracellular free drug. Degree of protein binding should spaces, such as in capillaries). They tend to be taken into account while relating these to have smaller volumes of distribution. concentrations of the drug that are active in vitro, e.g. MIC of an antimicrobial. Drugs highly bound to plasma protein To albumin To α1-acid glycoprotein (v) One drug can bind to many sites on the Barbiturates β-blockers albumin molecule. Conversely, more than one Benzodiazepines Bupivacaine drug can bind to the same site. This can give rise to displacement interactions among drugs SECTION 1 NSAIDs Lidocaine Valproic acid Disopyramide bound to the same site(s). The drug bound with Phenytoin Imipramine higher affinity will displace that bound with lower Penicillins Methadone affinity and tend to increase the concentration of Sulfonamides Prazosin its free form. This, however, is often transient Tetracyclines Quinidine because the displaced drug will diffuse into the Tolbutamide Verapamil tissues as well as get metabolized or excreted: Warfarin the new steady-state free drug concentration is only mar­ginally higher unless the displacement extends to tissue binding or there is concurrent (ii) The bound fraction is not available for inhibition of metabolism and/or excretion reduc­ action. However, it is in equilibrium with ing drug clearance. The overall impact of many the free drug in plasma and dissociates when displacement inter­actions is minimal; except when the concen­tration of the latter is reduced due the interaction is more complex. Moreover, two to elimination. Plasma protein binding thus highly bound drugs do not neces­sarily displace tantamounts to temporary storage of the drug. each other—their binding sites may not overlap, (iii) High degree of protein binding generally e.g. probenecid and indometha­cin are highly makes the drug long acting, because bound bound to albumin but do not dis­ place each fraction is not available for metabolism or other. Similarly, acidic drugs do not generally excretion, unless it is actively extracted by displace basic drugs and vice versa. liver or by kidney tubules. Glomerular filtration (vi)   In hypoalbuminemia, binding may be redu­ does not reduce the concentration of the free ced and high concentrations of free drug may form in the efferent vessels, because water is be attained, e.g. phenytoin and furosemide. also filtered. Active tubular secretion, however, Other diseases may also alter drug binding, e.g. removes the drug without the attendant solvent phenytoin and pethi­dine binding is reduced in → concen­ tration of free drug falls → bound uraemia; propranolol binding is increased in drug dissociates and is eliminated resulting pregnant women and in patients with inflam­ in a higher renal clearance value of the drug matory disease (acute phase reactant α1 acid- than the total renal blood flow (see Fig. 3.3). glycoprotein increases).  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 27 Drugs concentrated in tissues Skeletal muscle, heart — digoxin, emetine (bound to muscle proteins). Liver — chloroquine, tetracyclines, emetine, digoxin. Kidney — digoxin, chloroquine, emetine. Thyroid — iodine. Brain — chlorpromazine, acetazolamide, isoniazid. Retina — chloroquine (bound to nucleoproteins). Iris — ephedrine, atropine (bound to melanin). Bone and teeth — tetracyclines, heavy metals (bound to mucopolysaccharides of connective tissue), bisphosphonates (bound to hydroxyapatite). Adipose tissue — thiopentone, ether, minocycline, phenoxybenzamine, DDT dissolve in neutral fat due to high lipid-solubility; remain stored due to poor blood supply of fat. Tissue storage Drugs may also accumulate high concentration, e.g. tetracyclines on bone in specific organs by active transport or get and teeth, chloroquine on retina, streptomycin bound to specific tissue constituents (see box). on vestibular apparatus, emetine on heart and CHAPTER 2 Drugs sequestrated in various tissues are skeletal muscle. Drugs may also selectively bind unequally distributed, tend to have larger to specific intracellular organelle, e.g. tetracycline volume of distribution and longer duration of to mito­chondria, chloroquine to nuclei. action. Some may exert local toxicity due to Problem Directed Study 2.1 A 60-year-old woman complained of weakness, lethargy and easy fatigability. Investigation showed that she had iron deficiency anaemia (Hb. 8 g/dl). She was prescribed cap. ferrous fumarate 300 mg twice daily. She returned after one month with no improvement in symp- toms. Her Hb. level was unchanged. On enquiry she revealed that she felt epigastric distress after taking the iron capsules, and had started taking antacid tablets along with the capsules. (a) What could be the possible reason for her failure to respond to the oral iron medication? 2.2 A 50-year-old type-2 diabetes mellitus patient was maintained on tab. glibenclamide (a sulfonylurea) 5 mg twice daily. He developed toothache for which he took tab. aspirin 650 mg 6 hourly. After taking aspirin he experienced anxiety, sweating, palpitation, weak- ness, ataxia, and was behaving abnormally. These symptoms subsided when he was given a glass of glucose solution. (a) What could be the explanation for his symptoms? (b) Which alternative analgesic should have been taken? (see Appendix-1 for solutions)