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Dr. A. P. Muthal, GES’S Sir Dr. M. S. Gosavi College of Pharmaceutical Research and Education, Nashik 422005 PHARMACOKINETICS


INTRODUCTION Pharmacokinetics search for the answer of the question « what does the body do to the drug ?» . Pharmacokinetics studies; Absorption Distribution Metabolism (biotransformation) Excretion






GENERAL INFORMATION The first stage for the drugs to reach to their target organs is known as “ absorption ”. In fact, the absorption is the transportation of the drug across the biological membranes There are different mechanisms for a drug to be transported across a biological membrane: Passive (simple) diffusion Active transport Pinocytosis Facilitated diffusion


SIMPLE (PASSIVE) DIFFUSION The major role for the transportation of the drugs across the cell membrane is simple (passive) diffusion . The substances move across a membrane according to a concentration gradient . The concentration gradient is the factor that determines the route and rate of the diffusion. No energy is required. There is no special transport (carrier) protein. No saturation .


SIMPLE (PASSIVE) DIFFUSION The concentration gradient and the lipid solubility of the drug are the two main factors that determine the diffusion rate (speed) of the drug . Molecular weight of the high lipophilic drugs is not important as much as in the drugs that are soluble in water, BUT MW OVER 1000 is generally restrictive!!! The simple diffusion of the drugs with high solubility in water occurs via the aqueous pores found on the cell membrane (i.e. caffeine, ascorbic acid, acetylsalicylic acid, nicotinamide ). A queous pores do not play a major role in the simple diffusion of the drugs across the cell membrane.


ACTIVE TRANSPORT The transportation of the drug molecules across the cell membrane against a concentration or an electrochemical gradient . It requires energy (ATP) and a special transporter (carrier) protein . There is « transport maximum » for the substances (the rate of active transport depends on the drug concentration in the enviroment). FACILITATED DIFFUSION O ccurs by the carrier proteins . N et flux of drug molecules is from the high concentration to low concentration . No energy is required. Saturable .

Facilitated Diffusion & active transport:

Facilitated Diffusion & active transport

Facilitated Diffusion:

Facilitated Diffusion Integral proteins help molecules through membrane. 3 characteristics No energy is used Specific May become saturated Example: glucose Glucose molecules entering a cell using facilitated diffusion. Hint: “integral” means a part of, integral proteins go through the plasma membrane (also called transmembrane proteins). Perpherial proteins are only on the surface of the membrane.)

Active Transport :

Active Transport Need to move molecules up a concentration gradient. Uses cellular energy in from of ATP. Ions moving across membrane by active transport. Think: why does the cell need to use energy to pump the yellow balls out? Think about the concentration gradient… is it moving “uphill” or “downhill”?


FIRST ORDER KINETICS Fick’s law : Simple (passive) diffusion of the molecules from the cell membrane depends on Fick’s law. It represents the rate of simple diffusion for non-polar molecules . The rate of diffusion ( dn / dt ) is the change in the number of diffusing molecules inside the cell over time. D x A x (C out - C in ) Diffusion rate (dn / dt) = d x rate of diffusion = Ka x C out (or only C ) R ate of diffusion is proportional to the concentration of the drug at the administered area . ZERO ORDER KINETICS If the absorption occurs independently from the concentration of the drug ( rate of diffusion = Ka x C out , where C: C 0 :1), then it fits to the “zero order kinetics”. C oncentration has no effect on the diffusion rate of the drug , the absorption occurs in a constant speed .


THE KINETICS OF ACTIVE TRANSPORT Active transport occurs according to “ Michaelis-Menten kinetics ” Vmax x C Absorption rate (V ) = Km + C A ctive transport of molecules fits to the “first order kinetics ” until it reaches to transport maximum, but beyond the transport maximum then the transportation across the cell membrane of the active transported drug fits to “ zero order kinetics ”. The absorption according to the zero order kinetics occurs mainly in 2 situations: a) Active transport and facilitated diffusion ( if the transportation of the molecules have reached to a maximum level - transport maximum). b) Sustained release formulations.


PINOCYTOSI S The drugs which have MW over 900 can be transported by pinocytosis. It requires energy . The drug molecule holds on the cell membrane and then surrounded with plasma membrane and inserted into the cell within small vesicles .

Endocytosis Vs Exocytosis:

Endocytosis Vs Exocytosis Endocytosis: Cells form a vesicle to move large solid materials into the cell. Exocytosis: Cells moving large materials out of the cell. Hint: when have we used the prefixes ‘endo’ and ‘exo’ before? Look at our Latin roots.

Two types of endocytosis:

Two types of endocytosis Phagocytosis Solid objects moved into the cell. (“ phago ” mean to eat.) Pinocytosis: Liquids moved into the cell. (“ pino ” means to drink)


FACTORS THAT AFFECT THE ABSORBTION OF THE DRUGS A) DRUG-RELATED FACTORS Molecular size Lipid solubility Degree of ionization Dosage form Chemical nature (Salt/organic forms, crystal forms, solvate form etc.) Particle size Complex formation The pharmacological effect of the drug Concentration of the drug B) SITE of APPLICATION RELATED FACTORS Blood flow (at site of application) Area of absorption


DRUG-RELATED FACTORS Molecular size : There is a negative relationship between the molecular size and the absorption rate of the drugs. If the molecular size increases, absorption rate decreases. Lipid solubility: A parameter of the lipid solubility is called “ lipid-water partition coefficient (K) ” . If a lipid-water partition coefficient of a molecule is high, then the lipid solubility of the molecule is high . Degree of ionization: The lipid-water partition coefficient of an ionized drug molecule decreases . Degree of ionization is determined by “ Handersen-Hasselbach equation ” For weak acids: log (unionized drug / ionized drug) = pKa -pH For weak bases: log (unionized drug / ionized drug) = pH- pKa According to the equation, for weak acid drugs: if you increase the acidity of the medium (decrease the pH), the unionized form of the drug molecule increases so the absorption rate increases. The closer the pKa value to the pH of the body fluids (generally 7.4), the greater is the change in ionization degree .


DRUG-RELATED FACTORS ION TRAPPING : The distribution of a drug between two compartments separated by a membrane that allows simple diffusion depends on the pH difference between these compartments . At steady state, the concentration of unionized form of the drug molecules are the same; however the concentration of ionized form will not be equal at both sides because of the pH difference at both sides . i.e. accumulation of basic drugs in the milk (trapped)


DRUG-RELATED FACTORS Dosage form: Disintegration: Breaking up of the drug molecules into smaller pieces after administration (mostly oral) is called disintegration. Dissolution: Entering of the solid drug into a solvent to form a solution is called dissolution . S olution forms of a drug molecule (liquid dosage forms) are absorbed faster compared to unsolved (solid) forms of the same drug. Chemical nature (Salt/organic forms, crystal forms, solvate form etc.): Salt formations : Salt forms of weak acids (Na, K, Ca compounds) and weak base ( HCl , HBr compounds) drugs are more easily absorbed compared to their original (free) forms. Crystal forms : Amorphous structure of a drug has a higher dissolution rate compared to its crystalline structure. Solvate form : The hydrates are more soluble in water compared to other solvates .


DRUG-RELATED FACTORS Particle size : Decreasing the particle size of the drug fastens its dissolution so increases the absorption rate. Complex formation : The solubility of some low-soluble drug molecules can be increased by formation a complex with another drug molecule. The pharmacological effect of the drug : Effect on blood flow (vasoconstrictors, vasodilators, some cardiac drugs) in the absorption site , transition time of the drug in GI tract (drugs effecting the GI motility) . Concentration of the drug : Higher the concentration of the drug at the administration site, higher the absorption rate of that drug.


SITE of APPLICATION RELATED FACTORS Blood flow (at site of application): If the blood flow is high at the site of application, it causes an increase in absorption rate . Area of absorption : If the surface area that allows the absorption of the drug molecules is wide, then absorption rate from that surface becomes high .


ROUTES of DRUG ADMISTRATION Local administration Systemic administration


LOCAL ADMINISTRATION If the desired drug action site (target tissue) is placed on the surface of the body or if the site can be reached easily, i.e. by an injector needle, drugs can be applied locally. Epidermal (percutaneous ) Intracutaneous Conjunctival Intranasal Buccal Intrathecal Intrapleural Intrauterine Intracardiac Intravaginal I ntraarticular


LOCAL ADMINISTRATION Epidermal (percutaneous) : A pplication of some drugs over the surface of the skin in some dosage forms like, creams, lotions or solutions . There are some factors that affect the absorption of an epidermal administered drug : a ) Damage in the stratum corneum layer b ) Region of the body c ) High lipid-water partition coefficient and small molecular size d) Cleansing of the skin and friction


LOCAL ADMINISTRATION Intracutaneous : Generally used for allergic or bacteriological tests or application of local anesthetics . The volume over 0.1 ml is not generally desired in this kind of application.


Conjunctival : Ophthalmic solutions or ophthalmic ointments are applied locally for some eye or eyelid diseases. Intranasal: Nasal sprays or solutions can be used for nasal mucosa or paranasal sinus diseases (i.e. allergic rhinitis in spring). LOCAL ADMINISTRATION


LOCAL ADMINISTRATION Buccal : Generally used for the infectious diseases on the surface of the oral/ buccal mucosa or some dental problems or throat (i.e. mouthwashes for dental problems). Intrathecal : Some local anesthetics, analgesics or antibiotics are given to subarachnoid space between L3 and L4 vertebrate.


SYSTEMIC ADMINISTRATION If a widespread effect throughout the body is desired or if you can’t reach the target tissue to obtain a local effect, then systemic routes are used. There are 4 main routes for systemic administration of drugs : Enteral route Parenteral route Inhalation Transdermal route


ENTERAL ROUTE The drug is given to GI tract and absorbed from GI tract. There are 3 ways for enteral route : Oral Sublingual Rectal


ORAL ROUTE This is the most often used administration route of the drugs. This route is known to be the safest , easiest and the most economic way of administering drugs. Drug molecules are mostly absorbed from duodenum , jejunum and upper ileum . D isintegration and dissolution are the two main processes for the oral administered drugs before the absorption process. The absorption rate and absorption ratio of the orally administered drugs are closely related with the above two parameters.




ORAL ROUTE BIOAVAILABILITY : “In which extent (rate) the body benefits from the drug” is known as bioavailability. F or the orally administered drugs , bioavailability (systemic bioavailability) is the “ fraction of unchanged drug that reaches to the systemic circulation from the administration site (after passing through the liver)” . FIRST-PASS METABOLISM (pre-systemic elimination ): Examples : propranolol, tricyclic antidepressants, opioid analgesics like morphine and meperidine , some sex hormones.


ORAL ROUTE Drug Related Factors That Affect Bioavailability : Particle size, Crystalloid structure, Salt compound / free, Degree of hydration, Drug formulation affects the dissolution and disintegration. Patient Related Factors That Affect Bioavailability : Differences in first-pass metabolism, drug metabolism differences between individuals (pharmacogenomics), diseases that affect the GI motility, age, g ender , body weight, drug-drug or drug-food interactions


HIGH LOW BIOAVAILABILITY BIOAVAILABILITY Solutions…Suspensions…Capsule…Tablet…Coated tablet…Sustained Release (SR) tablets


ORAL ROUTE Physiological Factors That Affect the Absorption from GI Tract : S tomach emptying time Taking pills on a full or empty stomach G enerally doesn’t affect the absorption ratio but it affects the absorption rate . D rug-food interactions may be important. A bsorption of d rug s which are taken on an empty stomach starts earlier and it reaches the effective plasma concentration earlier than expected. Some drugs are recommended to be taken with food to minimize the irritant effect of the drug to the gastric mucosa. The motility of intestines diarrhea, constipation


SUBLINGUAL ROUTE Especially high lipophilic drugs are used by this route . Cardiac nitrates, Ca + channel blockers like nifedipine and some steroid sex hormone pills can be used by this route. There are 2 main advantages of this route : T he effect starts very quickly. S ystemic bioavailability of the drug is generally very high. RECTAL ROUTE Enema : as a liquid drug formulation R ectal suppositories : as a solid drug formulation . There is no first-pass metabolism in this route and the effect starts immediately.


PARENTERAL ROUTE There are 3 ways for parenteral route : Into veins** or arteries Intramuscular Subcutaneous Following IV injection, the effect starts immediately and the bioavailability is 100% . IM injection is applied to generally gluteal and deltoid muscles ; 5 ml is the maximum injection volume. For subcutaneous injections, the injection volume shouldn’t exceed 2 ml . Sometimes pellet implantation procedure can be performed for subcutaneous injections under the skin


INHALATION These drugs should be small particle sized with high lipid-water partition coefficient.


TRANSDERMAL Transdermal therapeutic systems (TTS, patch) are used generally for transdermal drug application. These are absorbed from the skin to circulation to obtain a systemic effect . These are generally high lipophilic drugs.

DRUG APPLICATION ROUTES: Advantages and Disadvantages:

DRUG APPLICATION ROUTES: Advantages and Disadvantages ROUTE ADVANTAGE DISADVANTAGE/WARNINGS Sublingual -The effect starts immediately, -NO first-pass elimination -The absorption may decrease if emesis happens. Oral -Easy, reliable, economic -First-pass elimination occurs, -Emesis, diarrhea, heavy constipation may cause decrease in absorption Rectal -The effect starts immediately, -NO first-pass elimination, -Suitable for patients with heavy emesis or when the oral route is not an appropriate route. -Unpleasant way of application -Risk of rectal bleeding -Increased bacteremia risk for immunosuppressive patients -Decreased absorption in diarrhea and constipation. Inhalation -The effect starts immediately, -suitable for general anesthetics and bronchodilators -Intubation and special equipment are required Intramuscular -The effect starts immediately, -Edema, local irritation or pain -Risk of infection Intravenous -The effect starts immediately, -Bioavailability is 100% -Irritation or pain -Risk of infection -Solution must be dissolved well -Risk of embolism Subcutaneous -Absorption is slower compared to im inj. -Edema, local irritation or pain -Volume shouldn’t exceed 2 ml -Risk of infection Intranasal -The effect starts immediately, -NO first-pass elimination. -Local irritation -Suitable for administration of small doses of drugs Transdermal -Enables for slow and long-term drug application -The effect starts very slowly -Local skin reactions can be seen Percutaneous -Suitable for local effect. -The effect starts very slowly -Local skin reactions can be seen




INTRODUCTION Distribution is passage of drug molecules to liquid compartments and tissues in the body via transportation across the capillary membrane. The body fluid compartments and volumes in which the drugs are distributed :


DISTRIBUTION The distribution of drugs can occur in 4 patterns throughout the body : Distribution only in plasma : HMW-Dextran , Evans blue dye, suramin Distribution to all body fluids homogenously : Small and non-ionized few molecules like alcohol , some sulfonamides . Concentration in specific tissues : iodine in thyroid; chloroquine in liver; tetracyclines in bones and teeth ; high lipophilic drugs in fat tissue Non-homogenous (non-uniform) distribution pattern : Most of the drugs are distributed in this pattern according to their abilities to pass through the cell membranes or affinities to the different tissues.


Factors Affecting the Distribution of Drugs: Diffusion Rate The Affinity of the Drug to the Tissue Components Blood Flow (Perfusion Rate) Binding to Plasma Proteins DISTRIBUTION

Factors Affecting the Distribution of Drugs:

Factors Affecting the Distribution of Drugs Diffusion Rate : There is a positive correlation between the diffusion rate of the drug and the distribution rate The Affinity of the Drug to the Tissue Components : Some drugs tend to be concentrated in particular tissues. Blood Flow (Perfusion Rate ) : There is a positive correlation between the blood flow in the tissue and the distribution of the drugs. Kidney , liver, brain and heart have a high perfusion rate (ml/100 g tissue/min) in which the drugs distribute higher; S kin , resting skeletal muscle and bone have a low perfusion rate. The total concentration of a drug increases faster in well-perfused organs .

Factors Affecting the Distribution of Drugs:

Factors Affecting the Distribution of Drugs Blood Flow (Perfusion Rate )

Factors Affecting the Distribution of Drugs:

Factors Affecting the Distribution of Drugs Binding to Plasma Proteins : The most important protein that binds the drugs in blood is albumin for most of the drugs. Especially, the acidic drugs (salicylates, vitamin C, sulfonamides, barbiturates, penicillin, tetracyclines , warfarin, probenesid etc.) are bound to albumin. Basic drugs (streptomycin, chloramphenicol, digitoxin , coumarin etc.) are bo u nd to alpha-1 and alpha-2 acid glycoproteins, globulins, and alpha and beta lipoproteins .

Properties of plasma protein-drug binding :

Properties of plasma protein-drug binding Saturable : O ne plasma protein can bind a limited number of drug molecule Non-selective : More than one kind of drug which has different chemical structures or pharmacological effects can be bound to the space on plasma protein Reversible : The bonds between the drug and plasma protein are weak bonds like hydrogen or ionic bonds. Bound fraction Unbound fraction

Properties of plasma protein-drug binding :

Properties of plasma protein-drug binding Only the free (unbound) fraction of the drug circulating in plasma can pass across the capillary membrane . Bound fraction serves as “drug storage ”. PLASMA INTERCELLULAR FLUID [DRUG]=1 mM [DRUG]=1 mM [DRUG+PROTEIN]=9 mM [TOTAL DRUG]=10 mM [TOTAL DRUG]=1 mM


DISTRIBUTION Storage (Concentration-Sequestration) of the Drugs in Tissues Stored drug molecules in tissues serve as drug reservoir . The duration of the drug effect may get longer. May cause a late start in the therapeutic effect or a decrease in the amount of the drug effect. Redistribution: Some drugs (especially general anesthetics ) w hich are very lipophilic, following the injection, firstly (initially ) distributes to the well-perfused organs like central nervous system . . Later , the distribution occurs to less perfused organs like muscles. At last , distribution of these drugs shifts to the very low-perfused tissues like adipose (fat) tissue. Redistribution results with the running away of the drugs from their target tissue and last their effect.


DISTRIBUTION Passage of the drugs to CNS : A bl ood -brain barrier exists (except some areas in the brain) which limits the passage of substances . Non-ionized, highly lipophilic, small molecules can pass into the CNS and show their effects . S ome antibiotics like penicillin can pass through the inflamed blood-brain barrier while it can’t pass through the healthy one. Passage of the drugs to fetus : Placenta doesn’t form a limiting barrier for the drugs to pass to fetus. T he factors that play role in simple passive diffusion, effect the passage of drug molecules to the fetus. Placental blood flow Molecular size Drug solubility in lipids Fetal pH (ion trapping) : fetal plasma pH: 7.0 to 7.2; pH of maternal plasma: 7.4 , so according to the ion trapping rules, weak basic drugs tend to accumulate in fetal plasma compared to maternal plasma .


Volume of DISRIBUTION Volume of Distribution = Amount of drug administered (dose) (mg) / concentration of drug in plasma (mg/ml ) Most of the times, volume of distribution calculated in this way is not equal to the real total volume of physiological liquid compartments in which the drug is distributed. So it may be called as “ apparent volume of distribution ( V d ) ”. Following a single-dose intravenous administration of a drug , log plasma concentration-time graph is plotted according to the values of plasma concentration taken at particular time points . Then the formula is : Volume of Distribution ( V d ) = Dose (iv) / C 0 ’ Also, you can calculate the volume of distribution from the same graph by using AUC (area under curve) and K e (rate constant for elimination) like : Volume of Distribution ( V d ) = Dose (iv) / (AUC x K e )


Volume of DISRIBUTION To know the volume of distribution ( V d ) value of a drug helps us to calculate : The amount of drug found in the body at a particular time from the analyzed plasma drug concentration. The drug dose (loading dose) that has to be given (required) to obtain a desired plasma drug concentration. To find the rate constant for elimination from the formula: K e = Clearence / V d


KINETICS OF DISTRIBUTION One compartment model : In this model, the whole body is considered to be the compartment (the volume) in which the drugs and/or the metabolites are distributed homogenously. Two compartment model : In this model, whole body is divided into two compartments regarding the distribution of drugs. Central compartment Drug elimination Peripheral compartment k1 k2 ke drug




INTRODUCTION The process of alterations in the drug structure by the enzymes in the body is called “biotransformation (drug metabolism)” and the products form after these reactions are called “drug metabolites” . S ome drugs which don’t have any activity in vitro, may gain activity after their biotransformation in the body. These types of drugs are called “ pro-drug ” or “ inactive precursor ”. Drug examples that gain activity after biotransformation (pro-drugs): PRO-DRUG EFFECTIVE METABOLITE Chloral hydrate Trichloroethanol Cortisone Hydrocortisone Enalapril Enalaprilate Lovastatin Lovastatin acid Clofibrate Clofibric acid L-DOPA Dopamine


INTRODUCTION Drug examples that is transformed to more active compounds after biotransformation: DRUG MORE ACTIVE METABOLITE Imipramine Desmethylimipramine Codeine Morphine Nitroglycerin Nitric oxide Losartan EXP 3174 (5-carboxylic acid metabolite) Thioridazine Mesoridazine


INTRODUCTION Drug examples that is transformed to less active compounds after biotransformation: Drug examples that is transformed to inactive metabolites after biotransformation DRUG LESS ACTIVE METABOLITE Aspirin Salicylic acid Meperidine Normeperidine Lidocaine De-ethyl lidocaine ( dealkylated ) DRUG INACTIVE METABOLITE Most of the drugs Conjugated compounds Ester drugs Hydrolytic products Barbiturates Oxidation products


INTRODUCTION The metabolites that are formed after biotransformation are generally more polar , more easily ionized compounds compared to the main (original) drug. So, these metabolites can be excreted from the body easily . Organs that biotransformation occurs : Liver** (the most important organ, the number and variability of the biotransformation enzymes are the highest) Lungs Kidney (tubular epithelium, sulphate conjugation) Gastrointestinal system (duodenal mucosa, MAO) Placenta Adrenal glands Skin Central nervous system Blood


ENZYMATIC REACTIONS The enzymatic reactions which the drugs are exposed to : Oxidation Reduction PHASE I Hydrolysis Conjugation PHASE II DRUG X (inactive or less active**, same activity, higher activity) Y (generally inactive) PHASE I PHASE II




OXIDATION REACTIONS Oxidation reactions are performed mostly*** by the enzymes in liver ( hepatocytes ) which are localized in the endoplasmic reticulum in microsomal fractions. These enzymes are cytochrome P450 mixed-functional oxidases . For the oxidation reactions, also molecular oxygen (O 2 ) and NADPH are required. Some special characteristics of microsomal P450 enzyme system : They are located in hepatic microsomes . The substrate specificity is low. Shows high affinity to high lipophilic molecules. NADPH and molecular oxygen (O 2 ) is required for its activity.


OXIDATION REACTIONS Cytochrome P450 is a “ hem ” containing protein. The active site of the protein is the Fe ion . This active site can bind the drug only if the Fe is oxidized in the form of Fe +3 . After the formation of enzyme-drug complex, an electron (e - ) released from NADPH by the enzyme NADPH- cytochrome P450 reductase is transferred to this complex. Reducted enzyme-drug complex binds molecular O 2 . Following this binding, enzyme-drug-O 2 complex breaks down into oxidized enzyme (oxidized free cytochrome P 450), water (H 2 O) and oxidized drug.




OXIDATION REACTIONS Cytochrome P450 enzyme is not an enzyme with only one type. P450 1, 2 and 3 (CYP1, CYP2 and CYP3) genes are involved in coding the enzymes which are responsible for the drug metabolism. Especially CYP3 type codes the enzymes that are responsible for the pre-systemic elimination of orally administered drugs. Drug metabolism by different CYP450 enzymes


OXIDATION REACTIONS Some main cytochrome P450 enzymes which play important role in drug metabolism Enzyme Drug examples CYP3A4 Most of the drugs CYP1A2 Caffeine, theophylline , paracetamol , propranolol … CYP2C9 Phenytoin , oral antidiabetics , NSAIDs… CYP2C19 Diazepam, propranolol , omeprazole … CYP2D6 Beta-blockers, some antidepressants, nicotine, opioid analgesics…


OXIDATION REACTIONS Hydroxylation reactions Aromatic, aliphatic and other hydroxylation Cytochrome P450 enzymes N-, O-, and S- dealkylation Cytochrome P450 enzymes Desulphurization -thio group is transformed to ketone, -sulfhydryl group turns into hydroxyl group Cytochrome P450 enzymes Oxidative deamination (amines with α-methyl) Cytochrome P450 enzymes S- and N-oxidation Cytochrome P450 enzymes N-hydroxylation Cytochrome P450 enzymes Oxidation reactions *** Alcohol dehydrogenase, Aldehyde dehydrogenase, Monoamine oxidase, tyrosine hydroxylase Performed by oxidases other than cytochrome P450 enzymes ( cytoplasmic ) Dehalogenation Dehalogenation enzymes


REDUCTION REACTIONS: These reactions are seen in fewer amounts compared to oxidation reactions. FAD is required additional to NADPH for these reactions. REDUCTION REACTIONS Aldehyde reduction Transformation to alcohol Cytoplasmic flavin containing enzymes Azo (N=N) reduction Transformation to amines Microsomal flavin containing enzymes Nitro reduction Transformation to amine or hydroxilamine Microsomal and cytoplasmic flavin containing enzymes


HYDROLYSIS REACTIONS A group is separated from the drug molecule, or drug molecule is broken down into two smaller molecules. HYDROLYSIS REACTIONS Esterase (hydrolysis) reactions Acetylcholine esterase, pseudo choline esterase, amidase Decarboxylation Decarboxylases Glycoside hydrolysis β-glycosidases O-dealkylation N-dealkylation S-dealkylation


CONJUGATION REACTIONS: Glucuronidation UDP- glucuronosyltransferases catalyze the reaction. This is a microsomal enzyme located in the endoplasmic reticulum of liver cell. Glucuronidation is the only conjugation reaction performed by microsomal enzymes. All the other conjugation reactions are performed by non- microsomal enzymes. Drugs like chloramphenicol , salicylic acid, morphine and endogenous compounds like steroids and bilirubin are conjugated with glucuronic acid. Glucuronic acid is a highly hydrophilic compound, so it decreases the lipid solubility of the drug after conjugation. Thus, excretion of the drug becomes easier.


CONJUGATION REACTIONS N- methylation O- methylation N- acetylation Sulfate conjugation ( sulfation ) Glutathione conjugation Conjugation with amino acids Conjugation with ribose or ribose phosphates

Factors That Affect The Biotransformation of Drugs:

Factors That Affect The Biotransformation of Drugs Induction or inhibition of microsomal enzymes Genetic differences Age Gender Liver diseases Environmental factors

Induction or inhibition of microsomal enzymes:

Induction or inhibition of microsomal enzymes Various drugs or environmental factors lead to increases in the activity of these enzymes by increasing the synthesis of microsomal enzymes. The importance of the enzyme induction is the increasing metabolism rate of the drugs and the reduction in their activities. On the other hand, some drugs stimulate the enzymes that inhibit themselves ( biochemical tolerance ). Unlike the enzyme induction, some drugs can inhibit the microsomal enzymes.


ENZYME     DRUG or SUBSTANCE THAT INDUCES THE ENZYME CYP1A2 Cigarette smoke, grilled meat (barbecue), aromatic polycyclic hydrocarbons, phenytoin CYP2C9 Barbiturates, phenytoin, carbamazepine, rifampin CYP2C19 NOT INDUCIBLE CYP2D6 NOT INDUCIBLE CYP3A4 Barbiturates, phenytoin, rifampin, carbamazepine , glucocorticoids, griseofulvin, INDUCERS


INHIBITORS   ENZYME     DRUG or SUBSTANCE THAT INHIBITS THE ENZYME CYP1A2 Cimetidine, ethinyl estradiol, ciprofloxacin CYP2C9 Amiodarone , isoniazid, co- trimoxazole , cimetidine, ketoconazole CYP2C19 Fluoxetine, omeprazole CYP2D6 Amiodarone , cimetidine, fluoxetine, paroxetine, haloperidol, diphenhydramine CYP3A4 Ketoconazole, erythromycin, , isoniazid, Ca channel blockers, red wine, grapefruit juice

Genetic differences:

Genetic differences Genetic polymorphism in some of the enzymes that play role in biotransformation of drugs can cause changes in the activity of the drugs which are metabolized by these enzymes. Hydrolysis of succinylcholine : Cholinesterase enzyme in plasma play important role in the hydrolysis of succinylcholine which is generally used for its muscle relaxant activity. The metabolism of succinylcholine slows down in the individuals who have atypical cholinesterase the activity of succinylcholine can rise up to hours in individuals who have atypical cholinesterase enzyme ( long duration (prolonged) succinylcholine apnea ) . Acetylation of isoniazid : Some individuals can metabolize this drug slowly ( slow acetylators ) and some faster ( rapid acetylators ). CYP2D6 polymorphism : C YP2D6 enzyme plays important role in the metabolism of many widely used drugs. this polymorphism can be also named as “ debrisoquine type polymorphism ”. The metabolism rate of some beta-blockers ( metoprolol , timolol ), some neuroleptics ( thioridazine , perphenazine ), and antitussives like dextromethorphan or codeine decrease significantly in the slow metabolizers.

Age & gender:

Age & gender I n newborns cytochrome P450 enzymes and glucuronosyltransferases are not sufficient . So, biotransformation of some drugs (diazepam, digoxin, acetaminophen, theophylline etc…) is very slow in newborns. Oxidation reactions performed by cytochrome P450 enzyme system are slower than normal metabolizing rates in elderly. The effect of aging on these enzymes can differ according to gender (reduction in enzyme activity is higher in old males) and between individuals . First-pass elimination shows a reduction with age as well. Metabolism rates of some drugs may change with gender. For example, succinylcholine and other choline esters and procaine are inactivated faster in men .

LIver Diseases:

L I ver Diseases Especially , the metabolism of drugs with a “high hepatic clearance ” decreases in liver diseases. This leads to accumulation of drugs in the body which are metabolized in liver, and eventually causes an increase in the effect and adverse effects as well. On the other hand, transformation of pro-drugs into their active forms occurs less in liver diseases. Induction of microsomal enzymes can occur with ; Biphenylles with polychlor DDT and some insecticides Benzopyrenes and other polycyclic aromatic hydrocarbons (products of burned coal and petroleum products) P olycyclic hydrocarbons in the cigarette smoke can induce some enzymes like CYP1A2 and CYP1A1 (For this reason, the metabolism rate of chlorpromazine, theophylline and imipramine is significantly high in heavy smokers). Diet (Cabbage and cauliflower can induce CYP1A1 and CYP1A2)


ENVIRONMENTAL FACTORS Especially pollutants can affect the microsomal enzymes . Induction of microsomal enzymes can occur with ; Biphenylles with polychlor DDT and some insecticides Benzopyrenes and other polycyclic aromatic hydrocarbons (products of burned coal and petroleum products) P olycyclic hydrocarbons in the cigarette smoke can induce some enzymes like CYP1A2 and CYP1A1 (For this reason, the metabolism rate of chlorpromazine, theophylline and imipramine is significantly high in heavy smokers). Diet (Cabbage and cauliflower can induce CYP1A1 and CYP1A2)


ENVIRONMENTAL FACTORS Inhibition of microsomal enzymes can occur with ; Carbon monoxide inhibits the microsomal enzymes. Grapefruit juice (some flavonoids in grapefruit juice can inhibit CYP3A4)


HEPATIC CLEARANCE It can be described as “ the volume of plasma cleared from the drug via metabolism in liver per unit time (ml/min)” It is an indicator of the metabolism rate of the drugs. Q C V C a Ca Q Cv Q = Total hepatic blood flow C a = Portal venous drug concentration + hepatic arterial drug concentration C v = Hepatic venous drug concentration


HEPATIC CLEARANCE C a -C v C a = HEPATIC EXTRACTION RATIO (E) Hepatic Clearance (CL H ) = Q x C a -C v C a (CL H ) = Q x E OR


HEPATIC CLEARANCE Drugs can be divided into 3 groups according to their hepatic clearances :   Drugs with high hepatic clearance (Drugs with high extraction ratio ) Drugs with low hepatic clearance (Drugs with low extraction ratio ) Other drugs


HEPATIC CLEARANCE Drugs with high hepatic clearance (Drugs with high extraction ratio ) : Generally these are high-lipophilic drugs Absorption ratios from the gastrointestinal tract is 100% or very close to 100%. The pre-systemic elimination of these drugs is very high; so because of this reason systemic bioavailability of these drugs are low. The ratio between the oral and parenteral dose of the drug is high (high difference in dose between oral and parenteral route) The bioavailability of these types of drugs shows considerable differences between the individuals. Hepatic blood flow has high influence on the metabolism rate of these drugs.


HEPATIC CLEARANCE Drugs with low hepatic clearance (Drugs with low extraction ratio ) : Metabolic rates of these drugs in liver are low. Elimination rate of these drugs are not affected considerably with the changes in hepatic blood flow. However, the induction/inhibition of metabolizing enzymes affects the metabolism rate. Other drugs : These drugs are the ones between the above two groups. Hepatic clearances of these drugs are affected in high amounts by both hepatic blood flow and metabolizing capacity of the biotransformation enzymes.








RENAL EXCRETION Drugs and metabolites are excreted from the kidneys by 2 ways . a ) Glomerular filtration b ) Tubular secretion Tubular reabsorption is not an excretion way; however there is no doubt that it effects the excretion of drugs from the body by the kidney . a) Glomerular filtration : Simple passive diffusion play role in glomerular filtration. T he filtration rate is 110-130 ml/min. T hey are filtered from the glomerulus into proximal tubules except the bound fraction of drug molecules to the plasma proteins. Because albumin cannot be filtered from the glomerulus, the drugs cannot pass through into the proximal tubules.


RENAL EXCRETION b) Tubular secretion : There are 3 important points about the tubular secretion mechanism of the drugs : Tubular secretion occurs mainly in the proximal tubules . Active transport is the main mechanism for tubular secretion. The efficiency (performance) of the excretion by tubular secretion is higher than glomerular filtration route. Clearance maximum in glomerular filtration is approximately 120 ml/min, whereas the clearance maximum of tubular secretion is about 600 ml/min.


RENAL EXCRETION Tubular reabsorption: This mechanism works in an opposite (counter) way by reducing the drug or metabolite excretion. Tubular reabsorption occurs mainly in distal tubules and partially in proximal tubules. It occurs by simple passive diffusion generally C hanging the pH value of the urine (making the urine acidic or basic) is going to change the ionization degree and the simple passive diffusion of the drug or the metabolite and lastly affect the excretion from the kidney. I f we make the urine acidic, the reabsorption of the weak acid drug from the renal tubules into the blood will increase, thus the excretion will decrease . In the opposite way, making the urine basic will cause an increase in the excretion of weak acid drugs.


These substances are generally secreted into the biliary ducts from the hepatocytes by active transport and finally they are drained into the intestines. Especially , highly ionized polar compounds (conjugation products) can be secreted into the bile in remarkable amounts. The most suitable molecular weight for the drugs to be secreted into the bile is approximately 500 KD . BILIARY EXCRETION


After biotransformation, metabolites are drained into the small intestine by biliary duct. Drug metabolites in the small intestine are broken down again in the small intestine and reabsorbed back reaching the liver by portal vein again . This cycle between the liver and small intestine is called the enterohepatic cycle . Especially the drugs which are metabolized by the conjugation reactions go under enterohepatic cycle . This is important, because enterohepatic cycle prolongs the duration of stay of the drugs in our body which leads an increase in the duration of their effect . D rug examples that go under the enterohepatic cycle in remarkable amounts. Chlorpromazine Digitoxin Indomethasin Chloramphenicol ENTEROHEPATIC CYCLE


Passage of the drugs into breast milk occurs generally by simple passive diffusion in breast feeding women. Drugs can be concentrated in milk according to the ion trapping phenomenon. Because the breast milk is more acidic than plasma, especially basic drugs tend to concentrate in breast milk. Milk / plasma ratios of a drug can be used as an indicator of the passage of some drugs into the breast milk. M ilk / plasma ratios for some drugs : Iodide : 65 Propyltiouracil : 12 Aspirin : 0.6-1.0 Penicillin : 0.1-0.25 Gaseous or the volatile substances can pass from the blood circulation into the alveoli by passing across the endothelium and epithelium of the alveolar membrane . Simple passive diffusion is the main mechanism for this transport . After passing into the alveoli, these substances can be excreted by expiration. EXCRETION from the LUNGS EXCRETION into BREAST MILK


ARTIFICIAL EXCRETION WAYS Hemodialysis is one of the options among the artificial excretion way for the drugs . It is used especially for the treatment of acute drug intoxications to eliminate the drug from the body.


ARTIFICIAL EXCRETION WAYS For the achievement of this system, there are some requirements : Plasma protein binding of the drug should be low (bound fraction should be low). Drug should not be stored in tissues (apparent volume of the drug should be low) The main elimination route of the drug should be from kidneys in unchanged ( without biotransformation ) form.




CLEARANCE It can be described as the volume of plasma cleared from the drug per unit time (ml/min). Total Body Clearance : It is the plasma volume cleared from the drug per unit time via the elimination of the drug from all biotransformation and excretion mechanisms in the body. Renal Clearance : It can be described as the rate of the excretion of a drug from kidneys . So in other words, renal clearance is the volume of plasma cleared from the non-metabolized (unchanged) drug via the excretion by kidneys per minute. There are four important factors that affect the renal clearance of the drugs: Plasma protein binding of the drug. Tubular reabsorption ratio of the drug. Tubular secretion ratio of the drug. Glomerular filtration ratio of the drug.


CL renal = [(Glomerular filtration rate + Tubular secretion rate) – Tubular reabsorption rate] / Cp If the renal clearance of the drug is higher than the physiological creatinine clearance (120-130 ml/min) , that time we can say that the tubular secretion helps and contributes the elimination of the drug additionally to filtration. In early newborns and newborns, glomerular filtration and tubular secretion mechanisms are immature and not sufficient. R enal Clearence (CL R ) = V x C U t x C P V = collected urine volume t = duration to collect the urine C P = plasma concentration of the drug C U = urine concentration of the drug


ELIMINATION HALF-LIFE (t 1/2 ) : It is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50% via different elimination mechanisms. t 1/2 = 0,693 x V d Clearance According to the above formulation ,   Elimination half-life is inversely (negatively) proportional with the clearance. How high the apparent volume of distribution of a drug, that high is the duration of stay of that drug in the body (Positive correlation between the half-life and the volume of distribution). If the apparent volume of distribution of the two different drugs is not the same; having the same clearance does not mean that the rate of elimination of these two drugs is equal to each other.


TIME DRUG LEFT % RATIO OF THE DRUG LEFT 0 x t 1/2 100 1 1 x t 1/2 50 1/2 2 x t 1/2 25 1/4 3 x t 1/2 12,5 1/8 4 x t 1/2 6,25 1/16 5 x t 1/2 3,125 1/32

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