drug elimination

is a defence mechanism that takes foreign substances out of the body and applied to any foreign substances, including medicines Drug elimination is the irreversible loss of drug by excretion and metabolism and or metabolism

reversible loss is of the chemically unchanged drug It occurs by taking this to urine. But sometimes we can have excreted drugs into bile, sweat, saliva, air, breast milk

conversion of the drug into different chemical species or metabolite. also called biotransformation mainly occurs in the liver also in the lungs, GI wall, blood, skin, kidney Metabolism (biotransformation) is a defence mechanism against undesirable foreign compounds, including drugs. The liver is the major site of drug metabolism. Most common routes are: Oxidation, reduction, hydrolysis: Phase I reactions Conjugation: Phase II reactions. Metabolites can be: Inactive, Toxic, Active, as the drug administered Exploited therapeutically: Administration of prodrugs relies on metabolism to form the active compound (the metabolite) from the inactive prodrug

we can predict drug concentration following uptake of a medicine We can predict how liver and renal disease may affect drug concentration.We have seen that lever. And again, these are the key organs involved in drug elimination.So if a patient has liver disease, renal dysfunction doesn’t mean that drug concentration will not decline as fast as he should We also be able to predict interactions that affect drug elimination. So there are interactions of drugs with other drugs, with components in food, with components of natural and herbal products that may change the elimination of a drug. We will want to know whether these interactions change the elimination of a drug to the point that are clinically relevant. we will be able to predict possibility in drug therapy due to the age because different age groups have different elimination capabilities for some drugs and also different population may have genetic differences in metabolizing enzymes, which may be, again, sometimes clinically relevant. The elimination process for each drug is described and quantify by its clearance.

the concentration that will be achieved after a dose, and so the effects and toxicity how the concentration of a drug will evolve with time - length of effects and toxicity the body exposure to the drug, and thus the effects and toxicity. for an absorbed dose.

The proportionality factor that relates the elimination rate of a drug with the drug concentration in blood (plasma). Volume of fluid (blood, plasma) that is completely cleared of drug per unit time. The units for clearance are volume/time (for example: mL/min, L/h) Example: ClDrug = 15 mL /min 15 mL of plasma (blood) are cleared of drug every minute

the rate in which is how much drug is taking per unit of time equals the rate out, which is how much drug is eliminated from the body per unit time Clearance, dosage regimen and steady state in a dose regimen Rate in (dose / time) = Rate out (Cl x Css)

The liver receives blood from: Hepatic artery (25%) Hepatic portal vein from various GI segments (75 %) Liver receives ≈ 1.5 L/min Blood arriving from both systems fuse and enter the liver capillaries called “sinusoids”. Blood leaves the liver via the hepatic vein that goes to the vena cava. The liver secretes bile acids, which empty to the common bile duct, and finally go to the gallbladder. Liver excretes and metabolizes drugs.

The liver is the organ with the largest metabolic capacity in the body Hepatic elimination processes include metabolism + biliary excretion Liver elimination works on endo- and exogenous substances. Lipophilic chemicals are usually metabolized into more hydrophilic entities and then, excreted into urine or bile. Drugs in blood may be: Bound to plasma proteins, Bound to blood cells Free (unbound). In principle, only free drug can enter the hepatocyte to be eliminated.

High Biliary Clearance: Polar MW > 350 Actively secreted Examples: Drugs: Pravastatine Metabolites: Glucuronide conjugates of drugs bilarlay excretion-bile duct- gallblader- intestine to feceaces or reacsopbed in to the blood

To be metabolized by one specific enzyme, a drug must: Have the right 3-D structure to interact with the “enzyme site” responsible for the reaction. Have a certain affinity for this site Enzyme-drug reactions are typically described by the Michaelis-Menten equation (see next slides). Drugs metabolized by the same enzyme can be metabolized at different rates. A drug can be metabolized by several enzymes. Understanding the “metabolic pathways” for a candidate is part of the drug discovery-development process Enzymatic metabolism: the P450 family is done by enzymes belonging to the cytochrome P450 family. There are other enzymes also involved in drug metabolism

Substrate specificity: A drug is normally a good substrate for one (some) enzymes but not for others. Kinetics: Enzymatic reactions follow Michaelis-Menten kinetics: Vmax is the maximum elimination rate (mass/time) KM is the Michaelis constant (mass/volume). KM is the concentration of drug at which the rate of the process equals ½ Vmax Drug metabolism is saturable: At high concentrations of drug the rate of elimination becomes constant and equal to Vmax For most drugs, saturation occurs at concentrations higher than those used for therapy. Drug interactions: Drug metabolism may be altered by diet, concomitant drugs and chemicals (food, natural products, tobacco). (See next slide for examples) Enzyme-inhibition: direct inhibition or by competition Enzyme-induction: A drug- or other chemical increases the activity of the enzyme (usually increased amount of enzyme): Enzyme inducers: smoking, insecticides, rifampin, phenobarbital Enzyme inhibitors: SSRIs inhibit the CYP2D6 system; grape fruit inhibits CYP3A4 Variability: Levels and activity of enzymes may differ among individuals resulting in different values of clearance for a same drug. This variability can be clinically relevant in some cases. genetic variations: fast metabolizer; slow metabolizer, ultra-fast metabolizer age, physio-pathology (hepatic disease)

Model used for describing enzymatic reactions Drug (D) form a complex (ED) with the enzyme (E). ED undergoes through biotransformation under the Metabolite (M) is formed. M leaves the enzymatic site and E can accept a another drug molecule. dC/dt = rate of metabolism, C = Drug concentrattion Vmax maximum rate of metabolism KM = Michaelis-Menten constant. It measures the affinity of the drug for the enzyme. When C = KM ; -dC/dt = 0.5*Vmax.

The value of an extraction ratio for a drug and eliminating organ can range from: 0 the drug is not eliminated as in this case: Centering = Cleaving 1 all the drug is eliminated as in this case: Cleaving = 0 EH = 0.25  25% of the drug entering the liver is eliminated. The hepatic extraction ratio is a the measure of the liver efficiency in eliminating the drug from the systemic circulation over a single pass through the organ.

The hepatic Clearance (ClH) measures the loss of drug across the liver and can be defined as: The volume of blood entering the liver from which all the drug is removed per unit time. That is, an CLH = 45L/h for a drug indicates that the liver can extract all the drug present in 45L of blood in one hour Or also as: The ratio between the hepatic elimination rate and the incoming concentration.

For some drugs the time required for: (a) leaving blood cells (b) dissociating from plasma proteins, (c) diffusing hepatic membranes (e) being metabolized by enzymes (d) being transported to bile is so short that most of the drug being delivered by the blood is removed by the liver. The hepatic extraction ratio (EH) or liver capacity to extract irreversibly these drugs is high and approaches 1. The Hepatic Clearance for these drugs gets close to the hepatic blood flow (~ 1.5 L/min = 90 L/h). In practical terms, an extraction ratio between 0.7-1 is considered as high. Partition out from blood cells, dissociation from plasma proteins, passage through membranes and into bile is very fast. The elimination process depends primarily on the blood bringing more drug. Clearance is perfusion rate-limited. Hepatic Clearance approaches hepatic Blood flow QH ≈ 1.5 L/min or 90 L/h (E =1) The hepatic clearance of drugs with high hepatic extraction ratio is: very sensitive to changes in blood flow (example during surgery, some disease states) relatively insensitive to changes in plasma binding, and enzymatic interactions Drugs with high hepatic extraction ratio have usually low systemic absorption because of they are metabolized extensively by First Pass effect. For a drug with EH = 0.8, 80% of an oral dose will be lost by hepatic first pas effect

For other drugs, the value of the extraction ratio is smaller. This can be due to a: (a) slow dissociation from RBC, (b) slow dissociation from plasma proteins, (c) slow diffusion into the hepatocytes (e) most frequent:slow enzymatic reaction (d) slow transport into the bile. practical terms, an extraction ratio 0.3 is considered as low. One of these processes rate limits the hepatic elimination of the drug: Partition out from blood cells, dissociation from plasma proteins, passage through membranes and into bile is slow. Most frequently: the drug is a poor substrate for the enzymes. Because the poor efficiency of the liver in eliminating the drug: Centering ≈ Cleaving ClH approximate ranges from 0 (EH=0) to 0.3x90L/h (EH=0.3) = 27 L/h Hepatic Clearance is: sensitive to changes plasma binding, enzymatic interactions insensitive to changes in blood flow

Elimination, metabolism and excretion definitions Cl concept and units. Links to drug therapy. Additivity of Cl: Total Cl = Hepatic Cl + Renal Cl 3. The liver as an eliminating organ. Biliary Clearance. 4. Concept of extraction ratio. For any eliminating organ: Clorgan = Qorgan x Eorgan Relation between extraction ratio, clearance and elimination rate Drugs with low and high extraction ratio. Impact on clearance and first pass effect. Metabolism can be described with Michaelis-Menten Kinetics • Some features of drug metabolism: Specificity, Saturation, Drug interactions (competition, enzymatic induction, inhibition), Variability.