Kinetics of ADME by Mukesh Jaiswal

KINETICS OF ADME

Submitted By:-Mukesh Jaiswal

APGDCRDehradun

Defined as the study of ADME of drugs and their relationship with its therapeutic and toxic effects.

The use of pharmacokinetic principles in optimizing the drug dosage for the patient need and achieving maximum therapeutic utility is called Clinical pharmacokinetics.

PharmacoKinetics

Routes can be broadly classified in to:-

Local Routes.

Systemic Routes.

Route of Drug Administration

Topical Route.

a. Skin. b. Mucous Membrane. √Mouth and Pharynx. √Eyes, Ear and Nose. √Bronchi and Lungs. √Urethra. √Vagina. √Anal canal.

Deeper Tissue.

Arterial Supply.

Local Routes

Oral Route. Sublingual Route. Rectal Route. Cutaneous. Inhalation. Nasal. Parenteral. √Subcutaneous. √Intramuscular. √Intravenous. √Intradermal Injection.

Systemic Routes

Defined as the process of movement of unchanged drug from the site of administration to systemic circulation.

Absorption of drug is directly proportional to drug concentration at the site of action.

Drug concentration at the site of action is directly proportional to therapeutic response.

Therefore Absorption of drug is directly proportional to the therapeutic response of drug.

Absorption of Drug

Concentration VS Time Graph

Cmax:- The point of maximum concentration of drug in plasma is called as peak and the concentration of drug at peak is known as peak plasma concentration.

tmax:- The time for drug to reach peak concentration in plasma.

AUC:- It represents the total integrated area under the plasma level-time profile and expresses the total amount of drug that comes in to systemic circulation after administration.AUC is expressed in mcg/Ml.

P’cokinetic Parameters

The velocity with which a reaction or a process occurs is called as its Rate.

The manner in which the concentration of drug influence the rate of reaction or process is called as the Order of reaction.

If C is the conc. Of drug A, the rate of decrease in C of drug A as it is changed to B can be described by a general expression as a function of time t.

dC= -KCn

dt

Rate, Rate Constants and Order of Reactions.

Where, K= rate constant

n= order of reaction

If n=0, it’s a zero order kinetics, if n=1 it is a first order kinetics and so on.

The three commonly encountered rate processes in physiologic systems are:-

√Zero order kinetics √First order kinetics

√Mixed order kinetics

Cont…

Zero order kinetics Defined as the one

whose rate is independent of the concentration of drug undergoing reaction i.e. the rate of reaction cannot be increased further by increasing the concentration of reactants.

Eg. Administration of a drug as a constant rate i.v. infusion.

Steady drug loss

Slope= -k0

First Order Kinetics Defined as whose rate is

directly proportional to the concentration of the drug undergoing reaction i.e. greater the concentration faster the reaction.

It is also called as monoexperimental rate process.

dC dt

c

It is a mixture of both first order and zero order kinetics.

It is also known as dose dependent kinetics.

Mixed Order Kinetics

Since oral route of drug administration is most common for systemically acting drug.

GIT plays important role in absorption of drug.

The GI lining constituting the absorption barrier allows most nutrients like glucose, amino acids, fatty acids, vitamins etc to pass rapidly through it in to the systemic circulation but prevents the entry of certain toxins and medicaments.

Gastrointestinal Absorption of Drug

The principal mechanism for transport of drug molecules across the cell membrane are:-

1. Passive Diffusion.2. Pore Transport.3. Facilitated Diffusion.4. Active Transport.5. Electrochemical Diffusion.6. Ion Pair Transport.7. Endocytosis.

Mechanism of Drug Absorption

Also called non ionic Diffusion.

Major Process for absorption of more than 90% of the drugs.

Here Drug molecules diffuses from a region of higher concentration to one of lower concentration until equilibrium is attained and the rate of diffusion is directly proportional to the concentration gradient across the membrane.

Also known as FICK’S LAW.

Passive Diffusion

dQ/dt=DAKm/w /h (CGIT –C)

Where:-

dQ\dt= rate of drug diffusion.

D= Diffusion Coefficient of the drug through the membrane.

A= Surface area of absorbing membrane.

Km/w= Partition Coefficient of the drug b/w the lipoidal membrane and aqueous GI fluid.

h= thickness of the membrane.

Cont…

It is also known as convective transport, bulk flow of filtration.

Important in the absorption of low molecular weight, low molecular size, and water soluble drug through narrow, aqueous-filled channels or pores in the membrane structure.

Examples are urea, water, and sugars.

Pore Transport

Pore Transport

It is carrier mediated transport system that operates the concentration gradients.

Much faster than passive diffusion.

Examples include entry of glucose into RBCs and intestinal absorption of vit B1 and B2 .

B1 +IF(intrinsic Factor)= B1-IF Complex (in intestine)

B1-IF Complex= B1 +IF (in Blood)

Faciliated Diffusion

Here drug is transported from a region of lower to one of higher concentration i.e. against the concentration gradient.

Required energy.

Can be inhibited by metabolic poisons that interfere with energy production.

Examples includes absorption of 5-fluorouracil, 5-bromouracil, methyldopa, levodopa.

Active Transport

Carrier

Also known as ionic diffusion.

Here the charge on the membrane influences the permeation of drugs.

The rate of permeation is in the following order.

Unionized > anions> cations

Electrochemical Diffusion

Here the cationic drugs or anionic drugs penetrates the membranes by forming reversible neutral complexes. Such phenomena is called ion pair transport.

In GI Lumen Cationic drug + Endogenous anion=neutral ion pair complex

In Blood Endogenous anion+ Free Drug

Ion Pair Transports

It is a minor transport mechanism which involves engulfing extracellular materials with in a segment of cell membrane to form a vesicles which then pinched off intra cellularly.

Endocytosis includes two types of processes:-

√ Phagocytosis (cell eating) √ Pinocytosis (cell drinking)

Endocytosis

Process of Endocytosis

Physicochemical properties of drug substances.

Dosage form characteristics and pharmaceutical ingredients.

Patient related factors.

Factors Influencing GI Absorption of Drugs

Drug solubility and dissolution rate. Particle Size and effective surface area. Polymorphism and amorphism. Lipophilicity of the drug. Salt form of drug. Drug stability.

Physicochemical Properties of Drug Substances

Disintegration time. Dissolution time. Manufacturing variables. Pharmaceuticals ingredients. Nature and type of dosage form. Product age and storage condition.

Dosage Form Characteristics and

Pharmaceutical Ingredients

Age. Gastric emptying time. Gastrointestinal pH. Disease state. Blood flow through GIT. Gastrointestinal contents. Pre systemic metabolism.

Patient Related Factors

Defined as the process which involves the reversible transfer of a drug b/w one compartments and another.

Distribution of Drugs

Drug distributed in the body Drug

metabolized

Drug in Plasma

Drug Excreted

Tissue Permeability of the drug.

Organ/tissue size and perfusion rate.

Binding of drug to tissue components.

Miscellaneous factors.

Factors Affecting Drug Metabolism

The tissue permeability of a drug depend upon the physicochemical properties of drug as well as the physiological barrier that restrict diffusion in to tissue.

Drug having molecular weight less than 500 to 600 Daltons easily cross the barriers and distributes easily.

Unionized drugs cross the barriers more easily than ionized one.

Tissue Permeability of the Drug

Lipophillic drugs are easily cross the barriers than hydrophillic drugs.

Weaker acids distributes more fasters than strong acids.

Thiopental distributes in CSF at a rate 80 times faster than salicylic acid.

Cont…

Perfusion rate is defined as the volume of blood that flows per unit time per unit volume of the tissue.

Drug distribution also depend upon the size of the organ/tissue.

Lists of organs in decreasing perfusion rate. lungs > kidney > adrenals > liver > heart > brain > muscles > skin

> fat > bone

Organ Size and Perfusion Rate

The phenomena of complex formation with proteins is called as protein binding of drug.

Binding of drugs falls in to 2 classes:-

1. Binding of drugs to blood components. √ Plasma Proteins √ Blood cells 2. Binding of drugs to extra vascular tissue

protein, fats, bones etc.

Binding of Drug to Tissue Components

The binding of drugs to various plasma proteins is reversible.

The order of binding of drugs to various plasma proteins is:-

albumin > α-1 acid glycoprotein > lipoprotein > globulins

For majority of drugs that bind to extra vascular tissues, in order of binding is:-

liver > kidney > lungs > muscles

Cont…

Age. Pregnancy. Obesity. Diet. Disease State. Drug interaction.

Miscellaneous Factors

Defined as the hypothetical volume of body fluid in to which a drug is dissolved or distributed.

Since the concentration of drug in plasma (C) is directly proportional to amount of drug in body (X),

X α C

or X = Vd C

Where Vd is apparent volume of distribution.

Vd = X/C

Volume of = Amount of drug in the body

Distribution Plasma Concentration of drug

Volume of Distribution

Defined as the conversion of drug from one chemical form to another.

The term metabolism is different from chemical instability.

For e.g. conversion of penicillin to penicilloic acid by the bacterial pencillinase and mammalian enzymes is metabolism but its degradation by the stomach acid to penicillenic acid is chemical instability.

Metabolism of Drug

It is also known as detoxification process

It normally results in p’cologic inactivation of drugs.

Sometimes yield the metabolites with equal activity. e.g. Prodrugs .

The decreasing order of drug metabolizing ability of various organ is:-

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

Brain, testes, muscles, spleen, etc also metabolize drugs to a small extent.

Cont…

These are the enzymes which helps in the metabolism of drugs.

Divided in to 2 categories:- √ Microsomal √ non-microsomal

The microsomal enzymes catalyze a majority of drug biotransformation reactions.

The no. of lipid soluble substrates can interact nonspecifically with the microsomal enzymes.

Drug Metabolizing Enzymes

R.T.Williams divided the pathways of drug metabolism reactions into 2 general categories:-

√ Phase I √ Phase ll

Phase l reactions are also known as Functionalization reactions or Transformation Reactions and Phase ll reactions also known as Conjugation reactions.

Chemical Pathways of Drug Metabolism

These reactions generally precedes phase ll reactions.

It includes Oxidative, Reductive, and Hydrolytic reactions.

In these reactions a polar group is either introduced or unmasked if already present.

The resulting product of phase l reaction is susceptible to phase ll reactions.

Phase l Reactions

Oxidative reactions increases hydrophilicity of xenobiotics by introducing polar functional groups such as –OH.

Cytochrome P-450 is the enzyme which transfers an oxygen atom to a substrates RH and convert it to ROH.

Reductive reactions are also capable of generating polar functional groups such as hydroxy and amino in to substrates.

Hydrolytic reactions makes a large chemical change in the substrates brought about by loss of relatively large fragments of the molecules.

Cont…

These reactions are also known as conjugation reactions.

These reactions generally involves covalent attachment of small polar endogenous molecules such as glucuronic acid, sulfates, glycine etc.

Attachment are either on the unchanged drugs or phase I products and form highly water soluble conjugates.

Also known as true detoxification reactions.

Phase ll Reactions

The enzymes involved in these reactions are called as transferases.

The phase ll reactions involved:-

√ conjugation with glucuronic acid. √ conjugation with sulfate moieties. √ conjugation with alpha amino acids. √ conjugation with glutathione. √ Acetylation reactions. √ Methylation reactions.

Cont…

Physicochemical properties of drugs.

Chemical factors.

√ enhance or inhibits by enzymes.

√ environmental chemicals.

Biological Factors . Physiologic factors.

√ Species difference. √ pregnancy.

√ Strains difference. √ Hormonal Imbalance. √ Sex Difference. √ Disease State. √ Age. √ Diet.

Factors affecting Metabolism of Drugs

Defined as the process whereby drug or their metabolites are irreversibly transferred from internal to external environment.

Principal organs of excretion are kidneys is known as renal excretion.

Other organs which are involved in excretion of drugs are lungs, biliary system, intestine, salivary glands and sweat glands is known as non renal excretion.

Excretion of Drugs

Almost all drugs and their metabolites are excreted by the kidneys.

The basis functional unit of kidney involved in excretion is the naphron.

Each kidney comprises of one million naphrons.

Each naphron is made up of :-

√ Glomerulus

√ Proximmal tubule √ Loop of henle √ Disttal tubule √ Collecting tubule

Renal Excretion of Drugs

Nephron

The principal processes that determine the urinary excretion of a drug are:-

√ Glomerular Filtration √ Active tubular Secretion √ Active or Passive Tubular Reabsorption

Rate of = Rate of + Rate of - Rate of

Excretion Filtration secretion Reabsorption

Process of Urinary Excretion

The sum of individual clearances by all eliminating organs is called as Total body clearance or Total systemic clearance.

Clearance is defined as the hypothetical volume of body fluids containing drug from which the drug is removed or cleared completely in a specific period of time.

Clearance(CL) = Elimination rate

Plasma drug concentration

Concept of Clearance

Defined as the volume of blood or plasma which is completely cleared of the unchanged drug by the kidney per unit time.

ClR = Rate of urinary excretion

Plasma drug concentration

Renal Clearance is the ratio of “sum of rate of glomerular filtration and active secretion minus rate of reabsorption” to “plasma drug concentration”.

ClR = rate of filtration + rate of secretion + rate of reabsorption

plasma drug concentration

Renal Clearance

Physicochemical properties of the drug.

Plasma concentration of the drug.

Distribution and binding characteristics of the drug.

Urine pH.

Blood flow to the kidneys.

Biological factors.

Drug interactions.

Disease states.

Factors Affecting Renal Excretion

The dose required in patients with renal failure can be calculated by:-

Normal Dose x Renal Failure

The dosing interval in hours can be computed from the following equation:-

Normal interval (in hours) RF

Dose Adjustment in renal failure

When the drug is eliminated by both renal and non renal mechanisms, the dose to be administered in patients with renal failure is obtained from:-

Normal dose [RF x Fraction excreted + Fraction eliminated] in urine nonrenally

Cont…

It is also known as extra renal routes.

The various non renal routes are:-

√ Biliary Excretion.

√ Pulmonary Excretion. √ Salivary Excretion. √ Mammary Excretion. √ Skin/Dermal Excretion. √ Gastrointestinal Excretion. √ Genital Excretion.

Non Renal Routes of Drug Excretion