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PharmacokineticsFate of Drugs

ADME

Dr Rammohan IMS, Pharmacology

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Pharmacokinetics

– The study of

Mechanisms and factors

associated with

the absorption,

distribution,

metabolism,

and excretion of

drugs

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Pharmacokinetics

The Four Cornerstones of Pharmacokinetics:

• Absorption

• Distribution

• Metabolism

• Elimination

Absorption and distribution are influenced by the formulation

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Pharmacokinetics– To reach their sites of action, drugs must overcome physiological

barriers. Mechanisms of Drug Absorption

• Filtration– The passage of small water-soluble substancesthrough aqueous channels» A function of hydrostatic or osmoticdifferences across the biological membrane.

• Passive diffusion• Requires passage across biological membranes– The passage of larger drug molecules acrossbiological membranes» A function of the concentration gradient of thedrug across the membrane

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Pharmacokinetics• Facilitated transport– The drug forms a complex with a component of the

biological membrane» The complex is carried through membrane, the drug is

released, and the carrier molecule returns to the membrane surface

» Does not require energy» Does not proceed against a concentration gradient.

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Active transport

– The drug forms a complex with a component of the biological membrane

» Characterized by selectivity, saturability, and competitive inhibition

» Requires energy

» Moves against a concentration gradient.

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• Endocytosis

– Some water-insoluble substances are engulfed by the cell membrane and are released into the cytoplasm

• Ex. Uptake of fats, starch, vitamins A,D,E,K, insulin.• Drug absorbed into lymphatic circulation bypassing first

pass metabolism.

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Absorption of drugs by various mechanisms

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Pharmacokinetics

– Most drugs are weak acids or weak bases

• Cross biological membranes mainly by passive diffusion

– Factors affecting the rate of diffusion:

» Molecular weight

» Concentration gradient of the drug across the

membrane

» Thickness, surface area, and permeability of

the membrane

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Pharmacokinetics

– Absorption

• A prerequisite for establishing adequate plasma drug levels.

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Drug AbsorptionDrug Absorption - Passive Diffusion• Most common means of drug absorption• Rate of passive diffusion across biological membranes is dependent

upon:

– Concentration difference across membrane• Usually very large

– Size• Relatively constant for most drugs (100-500 MW)

– Polarity• Variable (-OH, C=O)

– Ionization• Variable for drug (-COOH, -NH3)• Variable for environment (stomach, pH 1-3; duodenum,

pH 5-7; rest of sm. intestine, pH 7-8)• Majority of oral drug absorption occurs in duodenum.

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Physiological Factors Affecting Oral Drug Absorption

1) Gastrointestinal Motility– Decreased stomach emptying slows drug absorption– Can be decreased by food, disease, drugs (opioids)2) Gastrointestinal Blood Flow– Removes drug from site of absorption (conc. gradient)– Limiting factor for highly absorbed drugs (e.g. ethanol)3) Surface area– Approx 250m2 (adult male); 1000x > stomach– Most drug absorption occurs in small intestine (esp. duodenum)4) Metabolism and Efflux– Many drugs are metabolized in the intestinal wall– Many drugs are effluxed from enterocytes to gut lumen by transport

proteins5) Changes in pH of Gastrointestinal Tract– Affects polarity of drug– Can be altered by food, disease, other drugs (e.g. antacids)

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Drug Absorption - Summary• Most drug absorption occurs through passive absorption.

• Lipid soluble drugs are more readily absorbed than non-lipid soluble drugs.

• Non-ionized drugs are more readily absorbed than ionized drugs.

• Weak acids or weak bases are more readily absorbed in the small intestine than strong acids and bases.

- Stronger acids can be absorbed in stomach.

• Most drug absorption occurs in the small intestine.

- Large surface area

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BioavailabilityBioavailability refers to the rate and extent of absorption of a drug from

dosage form. It is a measure of the fraction (F) of administered dose of a drug that

reaches the systemic circulation in the unchanged form.

BA = Quantity of drug reaching systemic circulation Quantity of drug administered

– IV = 100%– Oral < 100%– Other routes ≤ 100%

– Example: Cyclosporine• Bioavailability IV = 100%• Bioavailability Oral = 25%• Therefore, oral dose 4 x IV dose

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Major Factors Affecting Drug Bioavailability

• First-Pass Metabolism (liverand intestine)• Efflux from enterocytes (activedrug transporters)• Physiochemical properties ofdrug that affect absorption(polarity, size, etc)• Nature of drug formulation(binders, solubilizers, etc)IV administration circumventsthese factors

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Pharmacokinetics

– Distribution• Process by which a drug reversibly leaves the site

of administration and distributed throughout the tissues of the body

• A prerequisite for most drugs to reach target organs in therapeutic concentrations

– Drugs, once again, must overcome physiological barriers» simple capillary endothelial barrier» simple cell membrane barrier» Blood-brain barrier» Blood-placental barrier» CSF barrier» Blood-testis barrier

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Drug DistributionExtent is dependent upon various factors– Blood flow (lung, kidney, liver > brain, skeletal muscle >

adipose, bone) – Ability of drug to traverse biological membranes.

– Organs and tissues vary widely in the proportion of blood flow

» Heart, liver, kidney, CNS receive the drug within minutes» Muscle, most viscera, skin, and fat require longer time– Degree of binding to blood proteins (e.g. serum albumin)• Distribution of drug to target organ/site is a critical

requirement for achieving a therapeutic benefit, but• Drug will be active at any organ/site if the receptor for the

drug is present and the drug achieves a sufficient local concentration. • e.g. Aspirin has analgesic effect in brain for headache relief and can also cause unwanted effects at other sites at common doses (e.g. GIT bleeding).

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• Drugs that selectively bind to plasma proteins/other blood components ex warfarin (less bound to extravascular tissues) have app Vd less than their real Vd.Vd of warfarin 10litres

• Drugs that bind selectively to extravascular tissues (less bound to blood and blood components) ex.chloroquine have app Vd greater than their real Vd.Vd of chloroquine 15000litres.these drugs leave the body slowly and generally more toxic.

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Distribution - Special Considerations• Consequence of physiochemical properties of drug and uniquephysiological properties of organ/tissue

– Bones/Teeth• Tetracycline has high affinity for calcium.

– Thyroid• Iodine-containing drugs are transported into this organ.

– Brain• Blood-brain barrier excludes most drugs

– Adipose• Can accumulate large amounts of lipid-soluble drugs• Release back into systemic circulation can occur with weight loss

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Distribution - Plasma Protein Binding• Many drugs bind reversibly with proteins in blood and other tissues• Binding to serum albumin in the blood is a common occurrence for drugs

(especially lipophilic drugs)!

Drug + Protein " Drug • Protein

• Albumin bound drug is not available to reach therapeutic target.

• Albumin bound drug can act as a reservoir of drug.

• Amount of free drug can be increased by:

– Displacement by another drug.

– Reduction of serum albumin levels (disease).

– Theoretically important for very highly bound drugs (>90%).

• In practice, no clinically relevant examples

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Pharmacokinetics

– Many drugs are

bound to plasma

proteins» Volume of =

distribution

Dose[Drug]plasma

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Drug Biotransformation• Most drugs are lipophilic and only partially ionized at physiological pH

– Organic compounds; Optimized for oral absorption

• Lipohilic drugs are poorly excreted by the kidney and liver

– Binding to plasma proteins inhibits glomerular filtration

– Reabsorption at renal tubules and biliary epithelium

– Partitioning into lipid-rich tissues (e.g. adipose)

• Biotransformation increases polarity and water solubility

• Metabolites often have less pharmacological activity; some drugs

(prodrugs) have more active or toxic metabolites (bioactivation)

• Liver is the major site for biotransformation of drugs; Intestine also has

significant metabolic capacity for some drugs (first-pass effect)

• Biotransformation can be divided into Phase I and Phase II metabolism

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Pharmacokinetics

– Metabolism• Metabolism fosters biotransformation intomore polar, more water-soluble fractions– Phase I (nonsynthetic reactions)» Cytochrome P450-dependent oxidation» Cytochrome P450-independent oxidation» Hydrolysis» Reduction– Phase II (synthetic reactions)» Transfer enzymes, both in the cytosol and theER of hepatocytes, couple (conjugate) drugsto endogenous macromolecules

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• Phase I/ functionalisation/asynthetic reactions

• Phase II/synthetic/ conjugation reactions

Phase I reactions: polar functional groups like OH, COOH, NH2, and SH groups are introduced.These include oxidative, reductive, and hydrolytic reactions.

o These reactions increase hydrophilicity.o Reduce stability.o Facilitate conjugation

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• Phase II reactions: These reactions involve covalent attachment of small polar endogenous molecules such as glucuronic acid, sulphates, glycine to either unchanged drugs or phase I products bearing functional groups like OH, COOH, NH2 and SH groups.

• Phase I metabolite may not be hydrophilic or may be pharmacologically inert but conjugation generally result in total loss of activity and high polarity.

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• Hence metabolism converts lipophilic water insoluble nonpolar drugs into polar and water soluble products that can be easily excreted by body.

• Biotransformation is essentially a detoxifying process.

Order of metabolism

• liver> lungs>kidneys>intestine>placenta>adrenals>skin.

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• Drug metabolising enzymes: liver enzymes are different from those that metabolise foods.

• These enzymes are versatile and non specific.

They are divided into:

1. Microsomal enzymes

2. Non microsomal enzymes

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Microsomal enzymes are the major type of liver enzymes.

• They are derived from rough endoplasmic reticulum.

• These enzymes catalyse oxidative, reductive, hydrolytic and glucuronidation reactions.

• Microsomal enzymes convert lipid soluble drugs into water soluble metabolites and readily excreted.

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Non microsomal enzymes present in soluble form in cytoplasm, attached to mitochondria and not to endoplasmic reticulum.

o These are non specific enzymes that catalyse few oxidative, reductive, hydrolytic, and conjugation reactions other than glucuronidation.

o These enzymes act on relatively water soluble drugs.

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Enzyme Inhibition and Induction

i. induction of drug metabolising enzymes:

The phenomenon of increased drug metabolising ability of enzymes by several drugs and chemicals is called enzyme induction and the agents which bring about such an effect are enzyme inducers.

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Inducers Drugs with enhanced metabolism

Barbiturates Phenytoin, cortisol, OC, testosterone

Phenytoin Cortisol, OC, tolbutamide

Rifampicin OC, tolbutamide, rifampicin

Cigarette smoke nicotine

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Consequences of enzyme induction:

1. Decrease in pharmacological activity of drugs.

2. Increased activity where metabolites are active.

3. Altered physiological status due to enhanced metabolism of sex steroids.

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ii. Inhibition of drug metabolising enzymes:

A decrease in drug metabolising ability of an enzyme is called enzyme inhibition.

Inhibitors Drugs with reduced metabolism

MAO inhibitors barbiturates, tyramine

Coumarins phenytoin

Allopurinol 6-mercaptopurine

PAS phenytoin, hexobarbital

Enzyme inhibition is more important clinically than enzyme induction for drugs with narrow TI. ex. Anticoagulants, antiepileptics.

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Drug Excretion

• Kidney– Quantitatively, most important route for parent drug andmetabolites– Active secretion into urine• Liver– Important for a number of drugs– Active secretion into bile• Other– Sweat, tears, reproductive fluids, milk, lung– Minor contributor– Passive diffusion

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• The principal renal mechanisms that are involved in the excretion of drugs are:

1. Glomerular filtration.2. Active tubular secretion3. Active tubular reabsorption• Glomerular filtration and active tubular secretion

increase concentration of drugs in lumen and facilitate excretion.

• Tubular reabsorption decrease the conc of drugs in lumen and prevents drugs movement to the outside.

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Excretion- Kidney• Drugs are eliminated from the body primarily

by the kidneys– Filtration at the renal glomerulus» A function of plasma protein binding and filtration

rate– Secretion into the proximal tubules» A nonselective carrier system for organic ions– Re-absorption from the tubular lumen and

transport back into the blood» Results in net passive re-absorption of unionized

drugs– Excreted into the urine

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pH-Dependence of Renal Excretion

• pH affects ionization and therefore, polarity of drugs• Ionized drugs are less effectively reabsorbed from loop of Henle• The renal elimination of ionizable drugs with pKa values within therange of urinary pH (5-8) can be increased or decreased by alteringurine pH• affects proportion of drug that is ionized (polar, excreted in urine) andnonionized (lipid-soluble, reabsorbed into blood).

• Example– Phenobarbital– Barbiturate with potent sedative properties– Weak acid– Alkalinization of the urine by infusion of sodium bicarbonate favoursionization of acid– increases renal excretion– Treatment for overdose

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pH-Dependence of Renal Excretion

• Amphetamine

– Stimulant used by competitive sprinters and

cyclists to enhance performance

– Weak base

– Acidification of urine (ammonium chloride, cranberry juice) increase ionization (polarity) of amphetamine.

– Less drug is reabsorbed; more drugs excreted in urine

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Pharmacokinetics– Excretion-GI tract• A relatively small number of drugs are excreted

primarily in the bile– Drugs enter the gastrointestinal tract in the duodenum

and pass through the small and large intestine before being excreted.

– Drugs may be reabsorbed in the small intestine and subsequently reenter the portal and then the systemic circulation.

» Enterohepatic recirculation• Drugs are also excreted into saliva, sweat, and tears

and through respiration

– Minor quantities

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Pharmacokinetics

– Clearance• Clearance (Cl)is hypothetical volume of body fluid

containing drugs from which the drug is removed/cleared completely in a specified period of time. Units are in ml/min.

• Cl=Elimination rate/Plasma drug conc • The rate of elimination of a drug from the body relative to

the concentration of the drug in plasma (mainly occurs in the kidney).

• Clearance is a function of glomerular filtration, secretion from the peritubular capillaries to the nephron, and reabsorption from the nephron back to the peritubular capillaries.

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– Half-life (t1/2) (elimination)• The time required to eliminate (metabolize

and excrete) 50% of the drug from the body.

• Determines the frequency of dosing required to maintain therapeutic plasma levels of a drug

• Half-life is determined by clearance (CL) and volume of distribution (VD) and the relationship is described by the following equation:

t1/2= 0.693 Vd/Cl

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• Distribution half-life» The time required to distribute 50% of the drug from plasma

throughout the body.

Cl is inversely related to Vd .

Drugs with large Vd poorly excreted in urine.

Drugs contained in blood compartment show higher clearance rates.

Drugs bound to plasma proteins or bound to tissues cannot be filtered by glomerulus.

• Nonrenal excretion: excretion through lungs, biliary system, intestine, salivary glands, sweat glands.

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