Biopharmaceutics and Pharmacokinetics Lecture 8 PDF

Biopharmaceutics and Pharmacokinetics LECTURE 8 Fundamental Pharmacokinetic Parameters Apparent Elimination rate Volume of constant (K) Distribution (Vd) Elimination half Clearance (Cl) life...

Biopharmaceutics and Pharmacokinetics LECTURE 8 Fundamental Pharmacokinetic Parameters Apparent Elimination rate Volume of constant (K) Distribution (Vd) Elimination half Clearance (Cl) life (t1/2) 19 Intravenous bolus administration: monitoring drug in plasma (one-compartment model) ▪ The one-compartment open model with IV bolus administration is the simplest pharmacokinetic model to study the fundamental pharmacokinetic parameters of a drug. Pharmacokinetic model for a drug administered by rapid intravenous injection. DB = drug in body; VD = apparent volume of distribution; k = elimination rate constant. ▪ The one-compartment open model with IV bolus dosing assumes that the drug is uniformly distributed within a single hypothetical compartment volume from which the drug concentration can be sampled and assayed easily. 3  1. Volume of Distribution Distribution of Drugs After entry into the systemic circulation, either by intravascular injection (IV) or by absorption from any extravascular sites (EV), the drug is subjected to several processes called disposition processes. Disposition is defined as the processes that tend to lower the plasma concentration of drug. The two major drug disposition processes are – 1. Distribution which involves reversible transfer of a drug between compartments. 2. Elimination which causes irreversible loss of a drug from the body. Elimination is further divided into two processes : (a)Biotransformation (metabolism) DINA.M.MAHDY, PHD 7th December 2023 (b)Excretion. 4  Distribution is the reversible transfer of a drug between the blood and the extravascular fluids and tissues. Steps in Drug Distribution Distribution of a drug present in the systemic circulation to the extravascular tissues involves the following steps: 1.Permeation of free unbound drug present in the blood through the capillary wall and entry into extracellular/ interstitial fluid (ECF) (occurs rapidly) 2. Permeation of drug present in the ECF through the membrane of tissue cells and into the intracellular fluid. DINA.M.MAHDY, PHD 7th December 2023 5 Factors Affecting the Distribution of Drugs 1. Tissue permeability of the drug: a.Physicochemical properties of the drug like molecular size, pKa, and o/w partition coefficient. b.Physiological barriers to the diffusion of drugs 2. Organ/tissue size and perfusion rate: 3. Binding of drugs to tissue components: a.Binding of drugs to blood components b.Binding of drugs to extravascular tissue proteins Apparent Volume of Distribution ❑It is defined as the hypothetical body fluid volume into which a drug should be dissolved or distributed to have the same concentration as the plasma concentration. ❑It is called apparent volume because all body parts equilibrated with the drug do not have equal concentration. DINA.M.MAHDY, PHD 7th December 2023 6 ❑ The volume of distribution is a fundamental pharmacokinetic parameter that describes how a drug distributes throughout the body relative to the concentration of the drug in the plasma i.e. It can indicate the extent of drug distribution into body fluids and tissues. ❑It is important to determine proper drug dosing regimens and interpret drug behavior in different physiological and pathological states. ❑Generally, dosing is proportional to the volume of distribution. For example, the larger the volume of distribution, the larger the dose required to achieve the desired target concentration. DINA.M.MAHDY, PHD 7 ❑ To understand how distribution occurs, you must have a basic understanding of body fluids and tissues ❑ The fluid portion (water) in an adult makes up approximately 60% of total body weight (~ 40- 42 L) and is composed of intracellular fluid (35%) (~ 22- 25 L) and extracellular fluid (25%) (~ 15-18 L) ❑ Extracellular fluid is made up of plasma (4%) (~ 4-6 L)and interstitial fluid (21%) (~10-12L) ❑ Interstitial fluid surrounds cells outside the vascular system. ❑ These percentages vary somewhat in a child. ❑ The body water is made up of 3 distinct compartments as shown in the Table ❑The volume of each of these real physiologic compartments can be determined by use of specific tracers or markers DINA.M.MAHDY, PHD 8 1. If a drug has a volume of distribution of approximately 15–18 L in a 70-kg person, we might assume that its distribution is limited to extracellular fluid, as that is the approximate volume of extracellular fluid in the body. 2. If a drug has a volume of distribution of about 40 L, the drug may be distributed into all body water because a 70-kg person has approximately 40 L of body water (70 kg × 60%) 3. If the volume of distribution is much greater than 40–50 L, the drug is probably concentrated in tissue outside the plasma and interstitial fluid. 4. If a drug distributes extensively into tissues, the volume of distribution calculated from plasma concentrations could be much higher than the actual physiologic volume in which it distributes. For example, by measuring plasma concentrations, ❑ It appears that digoxin distributes in approximately 400-500 L in an adult. Because digoxin binds extensively to muscle tissue, plasma levels are lower than concentrations in muscle tissues. ❑For other drugs, tissue concentrations may be lower than plasma concentration, so it may appear that these drugs are distributed in a relatively small volume (low volume of distribution). DINA.M.MAHDY, PHD 9  Determinatation of Vd Drug concentration in a compartment is defined as the amount of drug in a given volume, such as mg/L: During the entire time that the drug is in the body, elimination is taking place. So, if we consider the body as a tank with an open outlet valve, the concentration used to calculate the volume of the tank would be constantly changing. One way to calculate the apparent volume of drug distribution in the body is to measure the plasma concentration immediately after intravenous administration of bolus injection before elimination has had a significant effect. The concentration just after intravenous administration (at time zero, t0) is abbreviated as C0 The volume of distribution can be calculated using the equation: DINA.M.MAHDY, PHD 11 ❑C0 can be determined from a direct measurement or estimated by back extrapolation from concentrations determined at any time after the dose. ❑ If two concentrations have been determined, back extrapolation of a line containing the two values and extending through the y-axis can be drawn on semilog paper. ❑The point where that line crosses the y-axis gives an estimate of C0. ❑ Both the direct measurement and back- extrapolation approaches assume that the drug distributes instantaneously into a single homogeneous compartment DINA.M.MAHDY, PHD 12 Example: If 100 mg of drug is administered intravenously and the plasma concentration is determined to be 5 mg/L just after the dose is given, then calculate Vd. Vd= X / C V is the volume of distribution X is the amount of drug in body C is the concentration in the plasma Vd= 100 / 5 = 20L N.B volume of distribution can vary considerably from one person to another because of differences in physiology or disease states. DINA.M.MAHDY, PHD 13 For drugs administered extravascularly 𝐹 𝑋0 Vd= 𝐾𝑒 𝐴𝑈𝐶 where, Xo = dose administered, and F = fraction of drug absorbed into the systemic circulation. F is equal to one i.e. complete availability when the drug is administered intravenously. Ke: elimination rate constant AUC: area under concentration-time curve.  Volume of distribution (V) is an important indicator of the extent of drug distribution into body fluids and tissues. V relates the amount of drug in the body (X) to the measured concentration in the plasma (C). A large volume of distribution usually indicates that the drug distributes extensively into body tissues and fluids and vice versa. Two drugs can have the same volume of distribution, but one may distribute primarily into muscle tissues, whereas the other may concentrate in adipose tissues. DINA.M.MAHDY, PHD 15  Expressions of VD The apparent VD is a volume term that can be expressed as: a simple volume: (L) or standardized in terms of body weight: (L/kg) or in terms of percent of body weight: (%) ▪ In expressing the apparent VD in terms of percent of body weight, a 1-L volume is assumed to be equal to the weight of 1 kg. ▪ For example, if the VD is 3500 mL for a subject weighing 70 kg, the VD expressed as percent of body weight is 3.5Kg /70Kg x 100= 5% of body weight ▪ If VD is a very large number—>100% of body weight—then it may be assumed that the drug is concentrated in certain tissue compartments. ▪ VD of digoxin is 7.0 L/kg (estimated at 700% of body weight). Prof. Nabila Boraie 16 ❑ Approximate volumes of distribution for some commonly used drugs are shown in the Table below. ❑When V is many times the volume of the body, this indicates high drug concentrations in some tissues much greater than that in plasma (tissue binding). ❑ Examples include digoxin, diltiazem, imipramine, labetalol, metoprolol, meperidine, and nortriptyline. ❑The smallest volume in which a drug may be distributed is the plasma volume. Vd=42 L or 0.6 L/Kg (no binding) Vd> 42 L or 0.6 L/Kg (tissue binding) Vd< 42 L or 0.6 L/Kg (plasma protein binding) DINA.M.MAHDY, PHD 17 ▪ The apparent volume of distribution is a constant for a given drug. independent of the administered dose and independent of route of drug administration. ▪ The values of.Cp0 (y-axis intercept) are directly proportional to the administered dose of a drug (5, 10 and 25 mg dose); however, the ratio of Semilogarithmic plot of plasma concentration dose (DB0) over the initial plasma (Cp) versus time following three different doses concentration, Cp0 remains of drug as an intravenous bolus. Note the unchanged: deference in the intercepts, which are the initial plasma concentrations,(.Cp)0. Prof. Nabila Boraie 18  Significance of the Apparent Volume of Distribution ▪ The apparent volume of distribution is usually a property of a drug rather than of a biological system. ▪ It describes the extent to which a particular drug is distributed in the body tissues. ▪ The higher the value of the apparent volume of distribution, the greater is the extent to which the drug is distributed in the body tissues and or organs. ▪ The more lipophilic the nature of the drug, the greater will be the value of the apparent volume of distribution and the smaller will be the initial plasma concentration (e.g.,digoxin, diltiazem and metoprolol). ▪ Basic drugs, including tricyclic antidepressants and antihistamines, are extensively bound to extravascular tissues and are also taken up by adipose tissues. Their apparent volumes of distribution are large, often larger than the total body space; for example, ▪ The apparent volume of distribution of amphetamine is approximately 200 L (~ 3 L kg- 1). The relatively small doses and large volumes of distribution together produce low plasma concentrations, making quantitative Prof. Nabila Boraie détection in plasma 19 a difficult task. ▪ Conversely, if the drug is hydrophilic, the drug will penetrate to a lesser extent into tissue and, consequently its plasma concentration will be higher, and its volume of distribution will be smaller. ▪ Many acidic drugs, including salicylates, sulfonamides, penicillins, and anticoagulants, are either highly bound to plasma proteins or too water soluble to enter into cellular fluid and penetrate into tissues to a significant degree. These drugs, therefore, have low volumes of distribution and low tissue-to-plasma concentration ratios. ▪ Consequently, the binding of a drug to peripheral tissues or to plasma proteins will significantly affect the VD. ▪ Theoretical limits for the apparent volume of distribution will be as low as ≈ 5% of BW (equivalent to the volume of the plasma if the drug totally fails to penetrate the tissues or the drug is extremely hydrophilic) to as high as 10000 L or even greater. Prof. Nabila Boraie 20  VD in relation to body fluids Body water VD % of Comment BW compartment Plasma 4L 5.7 Drugs highly bound to plasma protein (Warfarin). High MW hydrophilic drugs (heparin) Extracellular fluids 14 L 20 Drugs distributed to extracellular fluids e.g. aminoglycosides Intracellular fluids 28L 40 Drugs distributed to intracellular fluids (more lipophilic low MW drugs Whole body fluids 42L 60 Drugs distributed to the whole-body fluids ( small water-soluble molecules e.g. alcohol) > 100 L >100 Drugs distributed to deep tissues( e.g. digoxin) or bound fat (phenobarbitone) Prof. Nabila Boraie 21 Certain generalizations can be made regarding the apparent volume of distribution of certain drugs: 1. Drugs that bind selectively to plasma proteins or other blood components, e.g. warfarin (i.e. those that are less bound to extravascular tissues), have an apparent volume of distribution smaller than their true volume of distribution. The Vd of such drugs lies between blood volume and TBW volume (i.e. between 6 to 42 litres) for example, warfarin has a Vd of about 10 litres. 2. Drugs which bind selectively to extravascular tissues, e.g. chloroquine (i.e. those that are less bound to blood components), have apparent volume of distribution larger than their real volume of distribution. The Vd of such drugs is always greater than 42 litres or TBW volume; for example, chloroquine has a Vd of approximately 15,000 litres Such drugs leave the body slowly and are generally more toxic than drugs that do not distribute deeply into body tissues. The Vd of various drugs ranges from as low as 3 litres (plasma volume) to as high as 40,000 litres (much above the total body size) DINA.M.MAHDY, PHD 7th December 2023 22 BINDING OF DRUGS TO BLOOD COMPONENTS (Plasma Protein-Drug Binding) ▪Following entry of a drug into the systemic circulation, the main interaction of drug in the blood compartment is with the plasma proteins which are present in abundant amounts and in large variety. ▪The binding of drugs to plasma proteins is reversible. ▪The extent or order of binding of drugs to various plasma proteins is: Abumin > α1-Acid Glycoprotein > Lipoproteins > Globulins Binding of Drugs to Human Serum Albumin ▪Human serum albumin (HSA), is the most abundant plasma protein (59 % of total plasma) with a large drug-binding capacity DINA.M.MAHDY, PHD 7th December 2023 23 TISSUE BINDING OF DRUGS (TISSUE LOCALIZATION OF DRUGS) The body tissues, comprise 40% of the body weight Hence, tissue-drug binding is much more significant than thought to be Importance of Tissue-drug binding 1.It increases the apparent volume of distribution of drugs in contrast to plasma protein binding which decreases it. This is because the parameter is related to the ratio of the amount of drug in the body to the plasma concentration of free drug and the latter is decreased under conditions of extensive tissue binding of drugs 2.Tissue-drug binding results in the localization of a drug at a specific site in the body (with a subsequent increase in biological half-life). This is more so because a number of drugs bind irreversibly with the tissues (contrast to plasma protein- drug binding); for example, oxidation products of paracetamol, phenacetin, chloroform, carbon tetrachloride and bromobenzene bind covalently to hepatic tissues. Factors influencing localization of drugs in tissues include: ❑ lipophilicity and structural features of the drug ❑ perfusion rate, pH differences, etc DINA.M.MAHDY, PHD 7th December 2023 24  Factors affecting Vd The physicochemical properties of the drug (lipophilicity, partition coefficient, M W, molecular size, degree of ionization, etc) Degree of tissue and protein binding Body composition and Blood flow Age, Pregnancy, and Diseases Importance and applications of Vd Calculation of the total amount of drug in the body relative to Cp. Calculation of loading dose when the target Cp is known to reach required therapeutic plasma concentration quickly Estimation of feasibility of hemodialysis in cases of drug overdose or in renal failure Dialysis is not useful for drugs with high Vd because of extensive tissue distribution. Dialysis is useful for drugs with low Vd where most of the drug is in circulation. 25 Thank you