Clinical Pharmacokinetics Renal Clearance LEC 7 PDF

CLINICAL PHARMACOKINETICS RENAL CLEARANCE Dr. Nermine Hamed, Pharm D, PhD  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. ◦ Drug elimination is usu...

CLINICAL PHARMACOKINETICS RENAL CLEARANCE Dr. Nermine Hamed, Pharm D, PhD  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. ◦ Drug elimination is usually divided into two major components: excretion and biotransformation. ◦ Drug excretion is the removal of the intact drug and drug metabolites. Nonvolatile 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 drug into bile, sweat, saliva, milk (via lactation), or other body fluids. ◦ Volatile drugs, such as gaseous anesthetics, alcohol, or drugs with high volatility, are excreted via the lungs into expired air. 2 DRUG ELIMINATION ◦ 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. ◦ The enzymes involved in biotransformation of drugs are located mainly in the liver. ◦ Other tissues such as kidney, lung, small intestine, and skin also contains biotransformation enzymes. ◦ Metabolites produced from biotransformation are also excreted. 3  DRUG CLEARANCE ◦ The term clearance describes the process of drug elimination from the body without identifying the individual processes involved. ◦ Clearance may be defined as the (fixed) volume of fluid removed from the drug per unit of time. The units of clearance are (volume/time: ml/min or L/hr). ◦ For example, if the Cl of a drug is 15ml/min in a patient and the drug has a VD of 12L, then from the clearance definition, 15ml of the 12L will be removed from the drug per minute. ◦ Clearance directly relates to the systemic exposure of a drug (eg, AUC), making it the most useful PK parameter clinically as it will be used to calculate doses to administer in order to reach a therapeutic goal in terms of exposure. ◦ When the PK behavior of the drug follows linear PK, clearance is a constant, whereas the rate of drug elimination is not. 4 DRUG CLEARANCE ◦ The Clearance of a drug Cl is directly related to the dose administered and to the overall systemic exposure achieved with that dose. 𝐹.𝐷𝑜𝑠𝑒 ◦ 𝐶𝑙 = 𝐴𝑈𝐶 ◦ Alternatively, Cl may be defined as the rate of drug elimination divided by the plasma drug concentration. 𝐸𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 ◦ 𝐶𝑙 = 𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛(𝐶𝑝) 𝑑𝐷𝐸 /𝑑𝑡 𝜇𝑔/𝑚𝑖𝑛 ◦ 𝐶𝑙 = ( ) = = 𝑚𝑙/𝑚𝑖𝑛 𝐶𝑝 𝜇𝑔/𝑚𝑙 ◦ The two definitions for clearance are similar because dividing the elimination rate by the Cp yields the volume of plasma cleared of drug per unit time. 5 DRUG CLEARANCE 𝑑𝐷𝐸 = 𝑘𝐷𝐵 𝑑𝑡 ◦ Where DB is the amount of drug in the body. 𝐷𝐵 = 𝐶𝑝. 𝑉𝐷 𝑑𝐷𝐸 = 𝑘𝐶𝑝 𝑉𝐷 𝑑𝑡 𝑑𝐷𝐸 /𝑑𝑡 𝑘𝐶𝑝 𝑉𝐷 𝐶𝑙 = ( ) = = 𝑘𝑉𝐷 𝐶𝑝 𝐶𝑝 0.693 ∗ 𝑉𝐷 𝐶𝑙 = 𝑡1/2 ◦ The clearance is the product of a volume of distribution VD and a rate constant k, both of which are constants when the PK is linear. ◦ As the plasma drug concentration decreases during elimination, the rate of drug elimination, dDE/dt, decreases accordingly, but clearance remains constant. Clearance is constant as long 6 as the rate of drug elimination is a first-order process.  PROBLEM I ◦ Drug A has a Cl of 15ml/min. Calculate the elimination rate for this drug when the plasma drug concentration, Cp, is 10µg/ml. 𝐸𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 ◦ 𝐶𝑙 = 𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛(𝐶𝑝) ◦ Now the plasma concentration dropped to 2µg/ml. Calculate the new elimination rate. 7  TOTAL BODY CLEARANCE ◦ The elimination rate constant (k) represents the total sum of all of the different rate constants for drug elimination, including the renal (kR) and liver (kH) elimination rate constant. ◦ Cl is the total sum of all of the different clearance processes in the body that are occurring in parallel, including clearance through the kidney (renal clearance ClR) and through the liver (hepatic clearance ClH) and others….. ◦ 𝐶𝑙 𝑇 = 𝐶𝑙𝑅 + 𝐶𝑙𝐻 + 𝐶𝑙𝑜𝑡ℎ𝑒𝑟 𝑅𝑒𝑛𝑎𝑙 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒: 𝐶𝑙𝑅 = 𝑘𝑅 𝑉 𝐻𝑒𝑝𝑎𝑡𝑖𝑐 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒: 𝐶𝑙𝐻 = 𝑘𝐻 𝑉 ◦ 𝑇𝑜𝑡𝑎𝑙 𝐵𝑜𝑑𝑦 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝐶𝑙 𝑇 = 𝑘. 𝑉 = 𝑘𝑅 + 𝑘𝐻 + 𝑘𝑜𝑡ℎ𝑒𝑟 ∗ 𝑉 8  Glomerular filtration and urine formation ◦ A normal adult male subject has a GFR of approximately 120 mL/min. About 180 L of fluid per day are filtered through the kidneys. In spite of this large filtration volume, the average urine volume is 1– 1.5 L per day. ◦ Up to 99% of the fluid volume filtered at the glomerulus is reabsorbed. Besides fluid regulation, the kidney also regulates the retention or excretion of various solutes and electrolytes. ◦ With the exception of proteins and protein-bound substances, most small molecules are filtered through the glomerulus from the plasma. ◦ The filtrate contains some ions, glucose, and essential nutrients as well as waste products, such as urea, phosphate, sulfate, and other substances. ◦ The essential nutrients and water are reabsorbed at various sites, including the proximal tubule, loops of Henle, and distal tubules. ◦ Both active reabsorption and secretion mechanisms are involved. The urine volume is reduced, and the urine generally contains a high concentration of metabolic wastes and eliminated drug products. 9  Glomerular filtration ◦ GLOMERULAR FILTRATION is a unidirectional process that occurs for most small molecules (MW < 500Daltons), including undissociated (nonionized) and dissociated (ionized) drugs. ◦ Protein-bound drugs behave as large molecules and do not get filtered at the glomerulus. The major driving force for glomerular filtration is the hydrostatic pressure within the glomerular capillaries. ◦ If the drug is eliminated only by filtration so renal clearance of the drug (ClR) will be equal to GFR (120ml/min). But this is only true if the drug is completely unbound to plasma protein. ◦ Only the fraction of the drug that is unbound to plasma protein (fu) will be filtered. 𝐷 + 𝑃 ⇌ 𝐷𝑃 ◦ Where D is the free drug (unbound), P is the plasma protein, DP is the bound drug. 𝐶𝑢 𝑓𝑢 = 10 𝐶𝑝  Glomerular Filtration ◦ Where fu is the fraction of the drug unbound to plasma protein, Cu is the unbound drug concentration, CpT is the total drug concentration (Cu +Cbound) 𝐶𝑢 = 𝑓𝑢. 𝐶𝑝𝑇 ◦ To estimate the rate of filtration at the glomerulus: 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 = 𝐺𝐹𝑅 ∗ 𝐶𝑢 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 = 𝐺𝐹𝑅 ∗ 𝑓𝑢 ∗ 𝐶𝑝 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝐺𝐹𝑅 ∗ 𝑓𝑢 ∗ 𝐶𝑝 = 𝐶𝑝 𝐶𝑝 𝐶𝑙𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 = 𝑓𝑢. 𝐺𝐹𝑅 11  Effect Of Plasma Protein Binding On Drug Concentration In Plasma And Volume Of Distribution ◦ For drugs that are highly bound to plasma protein, small changes in plasma protein binding will greatly affect drug plasma concentration. ◦ For a drug X, fu =0.1 (ie, drug is 90% bound to plasma protein, 10% unbound) ◦ If fu changed to 0.2 (due to displacement drug interaction or other causes) 𝐶𝑢 = 𝑓𝑢. 𝐶𝑝𝑇 𝐶𝑢 = 0.1 ∗ 10𝑚𝑔/𝐿 ◦ 𝐶𝑢 = 1𝑚𝑔/𝐿 ◦ 𝐶𝑢 = 0.2 ∗ 10𝑚𝑔/𝐿 ◦ 𝐶𝑢 = 2𝑚𝑔/𝐿 ◦ The free (active) drug concentration is doubled. ◦ EX. Warfarin. 12  Effect Of Plasma Protein Binding On Drug Concentration In Plasma And Volume Of Distribution ◦ For drugs that have less affinity to bind to plasma protein, small changes in plasma protein binding will unlikely have clinical consequences. ◦ For a drug Y, fu =0.5 (ie, drug is 50% bound to plasma protein, 50% unbound). If fu changed to 0.6 (due to displacement drug interaction or other causes) ◦ 𝐶𝑢 = 𝑓𝑢. 𝐶𝑝𝑇. 𝐶𝑢 = 0.5 ∗ 10𝑚𝑔/𝐿 ◦ 𝐶𝑢 = 5𝑚𝑔/𝐿 𝐶𝑢 = 0.6 ∗ 10𝑚𝑔/𝐿 ◦ 𝐶𝑢 = 6𝑚𝑔/𝐿 The free (active) drug concentration increased only by 20%. 13  Active Tubular Secretion ◦ Active tubular secretion is an active transport process. As such, active renal secretion is a carrier-mediated system that requires energy input, because the drug is transported against a concentration gradient. ◦ The carrier system is capacity limited and may be saturated. Drugs with similar structures may compete for the same carrier system. ◦ Two active renal secretion systems have been identified, systems for : ◦ (1) weak acids ◦ (2) weak bases. For example, probenecid competes with penicillin for the same carrier system (weak acids). Also quinidine and digoxin. ◦ Active tubular secretion rate is dependent on renal plasma flow. 14  ACTIVE TUBULAR SECRETION ◦ For a drug that is excreted solely by glomerular filtration, the elimination half-life may change markedly in accordance with the binding affinity of the drug for plasma proteins. ◦ In contrast, drug protein binding has very little effect on the elimination half-life of the drug excreted mostly by active secretion. ◦ Because drug protein binding is reversible, drug bound to plasma protein rapidly dissociates as free drug is secreted by the kidneys. ◦ For example, some of the penicillins are extensively protein bound, but their elimination half-lives are short due to rapid elimination by active secretion. 15  Tubular Reabsorption ◦ TUBULAR REABSORPTION occurs after the drug is filtered through the glomerulus and can be an active or a passive process. ◦ If a drug is completely reabsorbed (eg, glucose), then the value for the clearance of the drug is approximately zero. ◦ The reabsorption of drugs that are acids or weak bases is influenced by the pH of the fluid in the renal tubule (ie, urine pH) and the pKa of the drug. ◦ Both of these factors together determine the percentage of dissociated (ionized) and undissociated (nonionized) drug. ◦ Generally, the undissociated species is more lipid soluble (less water soluble) and has greater membrane permeability. The undissociated drug is easily reabsorbed from the renal tubule back into the body. 16 ◦ This process of drug reabsorption can significantly reduce the amount of drug excreted, depending on the pH of the urinary fluid and the pKa of the drug. ◦ The pKa of the drug is a constant, but the normal urinary pH may vary from 4.5 to 8.0, depending on diet, pathophysiology, and drug intake. ◦ In addition, the initial morning urine generally is more acidic and becomes more alkaline later in the day. ◦ Vegetable and fruit diets or diets rich in carbohydrates result in higher urinary pH, whereas diets rich in protein result in lower urinary pH.  Tubular Reabsorption ◦ Drugs such as ascorbic acid and antacids such as sodium carbonate may decrease (acidify) or increase (alkalinize) the urinary pH, respectively, when administered in large quantities. ◦ By far the most important changes in urinary pH are caused by fluids administered intravenously. Intravenous fluids, such as solutions of bicarbonate or ammonium chloride, are used in acid–base therapy. Excretion of these solutions may drastically change urinary pH and alter drug reabsorption and drug excretion by the kidney. ◦ Reabsorption is better if drug is non-ionized (Uncharged, lipid soluble, unpolarised) because it can cross the cell membrane. ◦ Excretion is better if the drug is more ionized (Charged, Lipid insoluble, Polarised, Water soluble) because it cannot cross the cell membrane. 18 PH OF URINE ◦ Acidic drugs are more ionized and not reabsorbed in alkaline urine ◦ Basic drugs are more ionized and not reabsorbed in acidic urine. ◦ Acidification and alkalinization of urine will facilitate the renal excretion of basic and acidic drugs respectively ◦ Alkalinize urine in Barbiturate and Aspirin poisoning. ◦ Acidify urine in Morphine, Amphetamine poisoning How to treat drug poisoning by renal secretion? ◦ Acidification of urine (in basic drug poisoning) ◦ Give Ammonium chloride( i.e. Morphine, Amphetamine overdose) ◦ Alkalinization of urine (in acidic drug poisoning) ◦ Give Sodium bicarbonate( i.e. Aspirin overdose) 19 In addition to the pH of the urine, the rate of urine flow influences the amount of filtered drug that is reabsorbed. The normal flow of urine is approximately 1–2 mL/min. Nonpolar and nonionized drugs, which are normally well reabsorbed in the renal tubules, are sensitive to changes in the rate of urine flow. Drugs that increase urine flow, such as ethanol, large fluid intake, and methylxanthines (such as caffeine or theophylline), decrease the time for drug reabsorption and promote their excretion. Thus, forced diuresis through the use of diuretics may be a useful adjunct for removing excessive drug in an intoxicated patient, by decreasing the extent of drug reabsorption in the kidney and increases the rate of drug excreted in the urine. ◦ QUESTION II A patient has overdosed on phenobartital. Phenobarbital is an acid. How to increase renal secretion of this drug? ◦ QUESTION III A patient who experiences migraines has accidentally overdosed with methysergide, a weak base of pKa=6.5. If urinary pH in this patient is 5.5, which of the following statements regarding elimination of methysergide from the body is accurate? ◦ A. Increase in urinary pH will increase excretion rate. ◦ B. Urinary excretion is already maximal, and changes in pH will have no effect. ◦ C. Attempts should be made to acidify the urine to at least 4 units below drug pKa. ◦ D. At urinary pH of 5.5, methysergide is 99% ionized. ◦ E. None of the above 21 RENAL CLEARANCE FROM A PHYSIOLOGIC POINT OF VIEW Renal clearance may be considered as the ratio of the sum of the glomerular filtration and active secretion rates less the reabsorption rate divided by the plasma drug concentration: ◦ 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑒𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 = 𝑟𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 + 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑎𝑐𝑡𝑖𝑣𝑒 𝑠𝑒𝑐𝑟𝑒𝑡𝑖𝑜𝑛 − 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑟𝑒𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑒𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑎𝑐𝑡𝑖𝑣𝑒 𝑠𝑒𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑟𝑒𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 = + − 𝐶𝑝 𝐶𝑝 𝐶𝑝 𝐶𝑝 𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒+𝑠𝑒𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒−𝑟𝑒𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 ◦ 𝐶𝑙𝑅 = 𝐶𝑝 ◦ 𝐶𝑙𝑅 = 𝐶𝑙𝑅𝐹 + 𝐶𝑙𝑅𝑆 − 𝐶𝑙𝑅𝑟 ◦ 𝐶𝑙𝑅 = (𝐺𝐹𝑅 ∗ 𝑓𝑢) + 𝐶𝑙𝑅𝑆 − 𝐶𝑙𝑅𝑟 22  Renal Clearance ◦ The kidney eliminates drugs by glomerular filtration and tubular secretion in the nephron. Once drug molecules have entered the urine by either of these processes, it is possible that the molecules may reenter the blood via a process known as tubular reabsorption. 23 Renal Clearance Process Active/Passive Location in Drug Drug protein Influenced by transport Nephron ionization binding Filtration Passive Glomerulus Either Only free Protein drug binding Secretion Active Proximal Mostly weak No effect Competitive tubule acids and inhibitors weak bases Reabsorptio Passive/Active Distal tubule Nonionized Not Urinary pH n applicable and flow 24 Urinary Excretion Data Parameters 25  Time of peak urinary excretion rate as an index of the rate of absorption Parameters considered important in Urinary excretion studies: ◦ 1. (dXu/dt) max: maximum urinary excretion rate (because most drugs are eliminated by first order rate process, the rate of drug excretion is dependent on the first-order elimination rate constant k and the amount of drug in the plasma A ◦ 2. (tu)max: time for maximum excretion rate ◦ 3. 𝑋𝑢∞ : 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑎𝑚𝑜𝑢𝑛𝑡 of drug excreted in the urine (it is related to the AUC of plasma level data) 26