Biopharmaceutics Lecture 1 - University of Kufa 2024-2025 PDF

University of Kufa Faculty of Pharmacy 2024-2025 Biopharmaceutics Year 4, Semester 1 Lecture 1 Sarmad Al-Edresi PhD Pharmaceutics MSc Pharmaceutical Technology 1 ...

University of Kufa Faculty of Pharmacy 2024-2025 Biopharmaceutics Year 4, Semester 1 Lecture 1 Sarmad Al-Edresi PhD Pharmaceutics MSc Pharmaceutical Technology 1  Topics Drug elimination; Drug clearance. Clearance models: Physiologic/organ clearance, Noncompartmental methods, Compartmental methods. The kidney; Renal clearance. Comparison of drug excretion methods. Reference text: Shargel L, Yu AB, (Eds.), Applied Biopharmaceutics and Pharmacokinetics; Latest edition. 2  Drug elimination Drugs are removed from the body by various elimination processes. Drug elimination refers to the irreversible removal of drug from the body by all routes of elimination. The declining plasma drug concentration observed after systemic drug absorption shows that: – The drug is being eliminated from the body but does not necessarily differentiate between distribution and elimination. 3 – It does not indicate which elimination  Drug elimination is usually divided into two major components: excretion and biotransformation. Drug excretion is the removal of the intact drug. Non-volatile and polar drugs are excreted mainly by renal excretion, a process in which the drug passes through the kidney to the bladder and ultimately into the urine. Other pathways for drug excretion may include the excretion of the drug into bile, sweat, saliva, milk (via lactation), or other body fluids. 4  Biotransformation or drug metabolism is the process by which the drug is chemically converted in the body to a metabolite. Biotransformation is usually an enzymatic process. A few drugs may also be changed chemically by a nonenzymatic process (e.g., ester hydrolysis). The enzymes involved in the biotransformation of drugs are located mainly in the liver. 5  The kidney, lung, small intestine and skin also contain biotransformation enzymes. Drug elimination in the body involves many complex rate processes. Although organ systems have specific functions, the tissues within the organs are not structurally homogeneous, and elimination processes may vary for each organ. The term clearance describes the process of drug elimination from the body or a single organ without identifying the individual processes involved. 6  Clearance may be defined as the volume of fluid removed of the drug from the body per unit of time. The units for clearance are sometimes in millilitres per minute (mL/min) but most often reported in litters per hour (L/h). The volume concept is simple and convenient because all drugs are dissolved and distributed in the fluids of the body. 7  Drug clearance Drug clearance is a pharmacokinetic term for describing drug elimination from the body without identifying the mechanism of the process. Drug clearance (also called body clearance or total body clearance, and abbreviated as or ) considers the entire body as a single drug-eliminating system from which many unidentified elimination processes may occur. 8  Instead of describing the drug elimination rate in terms of the amount of drug removed per unit of time (e.g., mg/h), drug clearance is described in terms of the volume of fluid removed from the drug per unit of time (e.g., L/h). There are several definitions of clearance, which are similarly based on the volume removed from the drug per unit of time. The simplest concept of clearance regards the body as a space that contains a definite volume of apparent body fluid (apparent volume of distribution, or ) in which the drug is dissolved. 9  Drug clearance is defined as the fixed volume of fluid (containing the drug) removed from the drug per unit of time. The units for clearance are volume/ time (e.g., mL/min, L/h). For example, if the of penicillin is 15 mL/min in a patient and penicillin has a of 12 L, then from the clearance definition, 15 mL of the 12 L will be removed from the drug per minute. Alternatively, may be defined as the rate of drug elimination divided by the plasma drug concentration. 10  This definition expresses drug elimination in terms of the volume of plasma eliminated of drug per unit time. This definition is a practical way to calculate clearance based on plasma drug concentration data. – where is the amount of drug eliminated and is the rate of elimination. 11  Rearrangement of previous Equation gives Equation below: The two definitions for clearance are similar because dividing the elimination rate by the yields the volume of plasma cleared of drug per minute, as shown in Equation above: A first-order elimination rate, , is equal to or. 12  Based on Equation below, substituting elimination rate for The clearance is the product of a volume of distribution, , and a rate constant, , both of which are constants when the PK is linear. As the plasma drug concentration decreases during elimination, the rate of drug elimination, , decreases accordingly, but clearance remains constant. Clearance is constant as long as the rate of drug elimination is a first-order process. 13  Clearance models The calculation of clearance from a rate constant (e.g., or ) and a volume of distribution (e.g., or ) assumes (sometimes incorrectly) a defined compartmental model. Clearance estimated directly from the plasma drug concentration-time curve using noncompartmental PK approaches does not need one to specify the number of compartments that would describe the shape of the concentration-time curve. 14  The various approaches for estimating a drug clearance are described in next Figure and will be explored one by one: 15  Compartmental methods Clearance is a direct measure of elimination from the central compartment, regardless of the number of compartments. The central compartment consists of the plasma and highly perfused tissues in which the drug equilibrates rapidly. The tissues for drug elimination, namely, kidney and liver, are considered integral parts of the central compartment. 16  Clearance is always the product of a rate constant and a volume of distribution. Different clearance formulas depend on the pharmacokinetic model that would describe appropriately the concentration- versus-time profiles of a drug product. The clearance formulas depend upon whether the drug is administered intravenously or extravascularly and range from simple to more complicated scenarios. 17 Physiologic/organ clearance Clearance may be calculated for any organ involved in the irreversible removal of drug from the body. Many organs in the body have the capacity for drug elimination, including drug excretion and biotransformation. The kidneys and liver are the most common organs involved in excretion and metabolism, respectively. Physiologic pharmacokinetic models are based on drug clearance through 18  For any organ, clearance may be defined as the fraction of blood volume containing drug that flows through the organ and is eliminated of drug per unit time. From this definition, clearance is the product of the blood flow () to the organ and the extraction ratio (). The is the fraction of drug extracted by the organ as drug passes through. 19  Noncompartmental methods Clearance is commonly used to describe first-order drug elimination from compartment models such as the one- compartment model, in which the distribution volume and elimination rate constant are well defined. Clearance estimated directly from the area under the plasma drug concentration time curve using the noncompartmental method is often called a “model- independent” approach. 20  It does not need any assumption to be set in terms of the number of compartments describing the kinetics or concentration- time profile of the drug under study. It is not exactly true that this method is “model-independent”. This method assumes that the terminal phase decreases in a log-linear fashion that is model-dependent, and many of its parameters can be calculated only when one assumes PK linearity. Referring to this method as “noncompartmental” is therefore more appropriate. 21  The kidney The liver and the kidney are the two major drug-eliminating organs in the body, though drug elimination can also occur almost anywhere in the body. The kidney is the main excretory organ for the removal of metabolic waste products and plays a major role in maintaining the normal fluid volume and electrolyte composition in the body. 22  To maintain salt and water balance, the kidney excretes excess electrolytes, water and waste products while conserving solutes necessary for proper body function. In addition, the kidney has two endocrine functions: 1. Secretion of renin, which regulates blood pressure. 2. Secretion of erythropoietin, which stimulates red blood cell production. 23 24 25  Renal clearance Renal clearance, , is defined as the volume that is removed from the drug per unit of time through the kidney. Renal clearance may be defined as a constant fraction of the central volume of distribution in which the drug is contained that is excreted by the kidney per unit of time. More simply, renal clearance is defined as the urinary drug excretion rate () divided by the plasma drug concentration (). 26  – where is the proportion of the bioavailable dose that is eliminated unchanged in the urine. Using the noncompartmental formula for studied earlier, we obtain: 27  Comparison of drug excretion methods Renal clearance may be measured without regard to the physiologic mechanisms involved in the process. Renal clearance may be considered the ratio of the sum of the glomerular filtration and active secretion rates less the reabsorption rate divided by the plasma drug concentration: 28  The renal clearance of a drug is often related to the renal glomerular filtration rate, GFR, when reabsorption is negligible and the drug is not actively secreted. The renal clearance value for the drug is compared to that of a standard reference, such as inulin, which is cleared completely through the kidney by glomerular filtration only. The clearance ratio, which is the ratio of drug clearance to inulin clearance, may give an indication for the mechanism of renal excretion of the drug 29  Further renal drug excretion studies are necessary to confirm unambiguously the mechanism of excretion. 30  Filtration only If glomerular filtration is the sole process for drug excretion, the drug is not bound to plasma proteins, and is not reabsorbed, then the amount of drug filtered at any time (t) will always be ×. If the of the drug is by glomerular filtration only, as in the case of inulin, then: =. represents all the processes by which the drug is cleared through the kidney, including any combination of filtration, 31 reabsorption and active secretion.  Filtration and active secretion For a drug that is primarily filtered and secreted, with negligible reabsorption, the overall excretion rate will exceed. At low drug plasma concentrations, active secretion is not saturated, and the drug is excreted by filtration and active secretion. At high concentrations, the percentage of drug excreted by active secretion decreases due to saturation. 32  Clearance decreases because excretion rate decreases. 33  Clearance decreases because the total excretion rate of the drug increases to the point where it is approximately equal to the filtration rate. 34 Thank you 35