Hawler Medical University Pharmacokinetics 4th stage Drug Clearance (Renal and Hepatic Clearance) Lec. -2- By: Dr. Raad A. Kaskoos Ph. D. Pharmaceutics Pharmaceutics Dept. Hawler Medical University College of Pharmacy

Drug Clearance (CL) Is a measurement of drug elimination from the body without reference to the mechanism of the process Generally, the body or organ tissues are regarded as a compartment of fluid with a definite volume (apparent volume of distribution) in which the drug is dissolved

Drug Clearance (CL), cont. Clearance is defined as the volume of blood or plasma from which the drug is completely removed in unit time It is expressed in a unit of ml/min or L/hr

Drug Clearance (CL), cont. Mathematically, clearance can be defined as the rate of drug elimination divided by the plasma drug concentration at that time point Clearance = excretion rate / plasma concentration

Total body clearance Is the sum total of all the clearance pathways in the body including renal clearance and hepatic clearance Clearance may be expressed on a per Kilogram body weight basis Therefore, to obtain clearance for an individual patient, multiply the clearance by the body weight of the patient

Renal Clearance Renal excretion of the drugs can be quantitatively described by means of renal clearance value for the drug Renal excretion is a major route of elimination for many drugs Drugs which are water soluble have low molecular weight (< 300) or are slowly biotransformed by the liver will be eliminated by renal excretion

Mechanisms of renal clearance The process by which a drug is excreted via the kidneys may include the combination of the following: Glomerular filtration Active tubular secretion Tubular reabsorption

Glomerular Filtration Is a unidirectional process which occurs for most small molecules (molecular weight < 500) including non-ionized and ionized drugs The major driving force is the hydrostatic pressure within the glomerular capillaries Glomerular filtration rate (GFR) is measured by using a drug that is eliminated by filtration only

Glomerular Filtration, cont. Example of such drugs are Insulin Glomerular filtration of drugs is directly related to the free protein-bound drug concentration in the plasma As the free drug concentration in the plasma increases, the glomerular filtration for the drug will increase proportionately

Active tubular (renal) secretion Is an active transport process Is a carrier mediated system which requires energy input The drug is transported against a concentration gradient The carrier system is capacity limited and may be saturated

Active tubular (renal) secretion, cont. Drugs with similar structures may compete for the same carrier system Two active renal secretion systems have been identified Systems for weak acids and weak bases Example: Probencid will compete with Penicillin for the same carrier system

Active tubular (renal) secretion, cont. Protein binding has very little effect on the elimination half-life of a drug excreted mostly by active secretion Drug protein binding is reversible process The bound drug and free drug are excreted by active secretion during the first pass through the kidney Example: Penicillins

Tubular reabsorption Occurs after the drug is filtered through the glomerulus Can be active or passive process If the drug is completely reabsorbed then the value for the clearance of the drug is approximately zero For partially reabsorbed drugs clearance values will be less than the GFR of 125-130 ml/min

Tubular reabsorption, cont. The reabsorption of acidic or basic drugs is influenced by the pH of the fluid in the renal tubule (urine pH) and the pKa of the drug Both of these factors together determine the percentage of dissociated (ionized) and undissociated (non-ionized) drug The undissociated species is more lipid soluble (less water soluble) and has greater membrane permeability and is easily reabsorbed from the renal tubule back in the body

Tubular reabsorption, cont. This process of drug reabsorption can 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 constant but the normal urinary pH may vary from 4.5 to 8.0 depending on diet, pathophysiology and drug intake Example: ascorbic acid and antacids such as sodium carbonate may alter urinary pH when administered in large quantity

Henderson – Hesselbalch equation It is used to calculate the percentage of ionized weak acid drug For weak acid drug: pH = pKa + Log (concentration of ionized drug) (concentration of unionized drug) Percent of drug ionized = 10 pH-pka 1 + 10 pH-pka

Henderson – Hesselbalch equation, cont. For weak base drug: pH = pKa + Log (concentration of unionized drug) (concentration of ionized drug) Percent of drug ionized = 1 + 10 pH-pka 10 pH-pka

Henderson – Hesselbalch equation, cont. This means a weak base drug reabsorbed if the urine pH is made alkaline and more lipid soluble unionized species are formed In contrast, acidification of the urine cause the weak base to become more ionized (form a salt) The salt form is more water soluble and less likely to be reabsorbed and excreted into the urine more quickly

Henderson – Hesselbalch equation, cont. In the case of weak acids, acidification of the urine causes greater reabsorption of the drug and alkalinization of the urine causes more rapid excretion of the drug In addition to the pH of the urine, the rate of urine flow influence the amount of filtered drug which is reabsorbed The normal flow of urine is approximately 1-2 ml/min.

Determination of clearance The clearance is given by the slope of the curve obtained by plotting the rate of drug excretion in urine (dDu / dt) against plasma drug concentration (C) since by the following equation: CL = dDu / dt C

Determination of clearance, cont. CL = dDu / dt C Where: dDu / dt = Rate of drug excretion in the urine C = Plasma drug concentration

Determination of clearance, cont.

CLT = CLR + CLH + CLothers Total body clearance The total body clearance (CLT ) is an additive property of individual organ clearance. Hence, CLT = CLR + CLH + CLothers Where: CLT = Total clearance CLR = Renal clearance CLH = Hepatic clearance

Body clearance of drugs that follow two-compartment model: 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 drug equilibrates rapidly The tissues for drug elimination (kidney and liver) are considered integral parts of the central compartment

Body clearance of drugs that follow two-compartment model, cont. The overall elimination rate constant Ke represents elimination from the central compartment The total body clearance is the product of Ke times the volume of the central compartment Vc Others method for calculating total body clearance considers either instantaneous clearance or steady state clearance depending on which volume of distribution is chosen

Total body clearance of drugs after IV infusion Clearance can be obtained by: CLT = K0 / C∞ Where: CLT = Total clearance K0 = is the rate of infusion C∞ = is the steady state plasma drug concentration

Clearance for drugs involving active secretion 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 decreased due to saturation Clearance decreases since excretion rate decreases, and till the total excretion rate of the drug decreases to the point where it is approximately equal to the filtration rate

Clearance for drugs involving active secretion, cont.

Relationship of half-life (t1/2), apparent volume of distribution and clearance: Total body clearance CLT is a useful index of measurement of drug removal and may be used in preferentially to the elimination half-life (t1/2) Total body clearance takes into account changes in both the apparent volume of distribution Vd and half-life (t1/2) The volume of distribution Vd is important in the calculation of the loading dose

Relationship of half-life (t1/2), apparent volume of distribution and clearance, cont. While the total body clearance CLT is important for calculation of the maintenance dose Total body clearance CLT may be calculated by the ratio FX0 / (AUC)0 which is considered a model independent method and assumes no particular pharmacokinetic model for drug elimination

Relationship of half-life (t1/2), apparent volume of distribution and clearance, cont. Clearance can be obtained by: CLT = Ke Vd And Ke = 0.693 / t1/2 CLT = 0.693 Vd / t1/2 t1/2 = 0.693 Vd / CLT

Protein bound drugs are not eliminated by glomerular filtration Only the free drug is excreted by a linear process The bound drugs are usually excreted by active secretion CLR = rate of unbound drug excretion / concentration of unbound drug in the plasma There are certain limitations with this equation because the drug excretion is usually determined after collecting urine samples:

Protein bound drugs, cont. The drug excreted in the urine is the sum of drug excreted by active tubular secretion and by passive glomerular filtration It is not possible to distinguish the amount of bound drug actively secreted from the amount of drug excreted by glomerular filtration For most drug studies the total plasma drug concentration (free plus bound drug) is used in clearance calculations

Clearance Ratio The actual physiologic process for the renal clearance of a drug is not generally obtained by direct measurement By comparing the clearance value for the drug to that of a standard reference drug (such as inulin which is cleared through the kidney by glomerular filtration only), the physiologic clearance process for the first drug may be inferred, for example:

Clearance Ratio, cont.

Any Questions?

The End… Thank you….