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Pharmacokinetics. ผศ.มนุพัศ โลหิตนาวี [email protected] [email protected] Outline. Introduction Physicochemical properties Absorption, Bioavialability, routes of admistration Distribution Biotransformation (Metabolism) Excretion Clinical pharmacokinetics.

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Pharmacokinetics

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Pharmacokinetics

ผศ.มนุพัศ โลหิตนาวี

[email protected]

[email protected]


Outline

  • Introduction

  • Physicochemical properties

  • Absorption, Bioavialability, routes of admistration

  • Distribution

  • Biotransformation (Metabolism)

  • Excretion

  • Clinical pharmacokinetics


Components of pharmacokinetics

  • Input, dosing by using routes of administration

  • Pharmacokinetic processes (figure 1, drawing)

    • Absorption

    • Distribution

    • Biotransformation (Metabolism)

    • Excretion


Cell membrane

  • barrier of drug permeation (drawing), with semipermeable property

  • factors affecting drug across cell membrane

    • cell membrane properties

    • physicochemical properties of drugs


Cell membrane

  • physicochemical properties of drugs

    • size and shape

    • solubility

    • degree of ionization

    • lipid solubility


Cell membrane

  • Characteristics of Cell membrane

    • Lipid bilayer: mobile horizontally, flexible, high electrical resistance and impermeable to high polar compounds

    • protein molecules function as receptors or ion channels or sites of drug actions.


Diffusion across the cell membrane

  • Passive transport (drawing)

    • higher conc to lower conc area

    • energy independent

    • at steady state both sides have equal conc.(non electrolye cpds)

    • electrolyte: conc. of each side depends on pH (fig 2)

    • weak acid and weak base


Diffusion across the cell membrane

  • Carrier-mediated membrane transport (drawing)

    • lower conc to higher concentration area (agianst concentration gradient)

    • structure specific

    • rapid rate of diffusion

    • Active and Facillitated transport


Diffusion across the cell membrane

  • Active transport

    • energy dependent

    • structure specific, inhibited by structure-related cpds, saturable

  • Facillitated transport

    • energy independent

    • structure specific, inhibited by structure-related cpds, saturable


Saturable process

  • Drawing

  • almost all protein-mediated process in our body can occur this process saturation not only transport system but also others such as enzymatic reaction, drug-ligand binding and so on.

  • because functional protein molecules are limited.


Drug absorption

  • Parameters in drug absorption

    • Rate constant of drug absorption (Ka)

    • Bioavialability (F)

  • Anatomical aspects affecting absorption parameters (Drawing)

    • GI tract (metabolzing organ and barrier of drug movement)

    • Liver (portal and hepatic vien, excretion via biliary excretion)

    • cumulative degradation so called “First pass effect”


Drug absorption

  • Factors affecting drug absorption (Drawing)

    • Physicochemical properties of drugs

    • pH at site of absorption

    • Concentration at the site of administration

    • Anatomical and physiological factors

      • Blood flow

      • Surface area


Routes of administration

  • Enteral and parenteral routes

  • Pros and cons between Enteral and parenteral


Enteral administration

  • Pros

    • most economical,

    • most convenient

  • Cons

    • high polar cpds could not be absorbed

    • GI irritating agents

    • enzymatic degradaion or pH effect

    • Food or drug interaction (concomitant used)

    • cooperation of the patients is needed

    • first pass effect due to GI mucosa


Parenteral administration

  • Pros

    • Rapidly attained concentration

    • Predictable conc by the calculable dose

    • Urgent situation

  • Cons

    • Aseptic technic must be employed

    • Pain

    • limited self adminstration

    • More expensive


Enteral administration

  • Common use of enteral administration

    • Oral administration

    • Sublingual administration

    • Rectal administration


Enteral administration

  • Concentrion-time course of oral administration (Drawing)

  • Rapid increase in plasma conc until reaching highest conc and subsequent decrease in plasma conc

  • Drawing (concept of MTC and MEC)

    • Absorption phase

    • Elimination phase


Enteral administration

  • Prompt release: the most common dosage form

  • Special preparation: Enteric-coat, SR

  • SR, Controlled release: Purposes and limitation


Enteral administration

  • Sublingual administration

    • Buccal absorption

    • Superior vana cava directly: no first pass effect

    • Nitroglycerin (NTG): highly extracted by the liver, high lipid solubility and high potency (little amount of absorbed molecules be able to show its pharmacological effects and relieve chest pain).


Enteral administration

  • Rectal adminstration

    • unconscious patients, pediatric patients

    • 50% pass through the liver and 50% bypass to the inferior vena cava

    • lower first pass effect than oral ingestion

    • inconsistency of absorption pattern

    • incomplete absorption

    • Irritating cpds


Parenteral administration

  • Common use of parenteral administration

    • Intravenous

    • Subcutaneous

    • Intramuscular

  • Simple diffusion

  • Rate depends on surface of the capillary, solubility in interstitial fluid

  • High MW: Lymphatic pathway


Parenteral administration

  • Intravenous

    • precise dose and dosing interval

    • No absorption (F=1), all molecules reach blood circulation

    • Pros: Calculable, promptly reach desired conc., Irritating cpds have less effects than other routes

    • Cons: unretreatable, toxic conc, lipid solvent cannot be given by this route (hemolysis), closely monitored


Parenteral administration

  • Subcutaneous

    • suitable for non-irritating cpds

    • Rate is usually slow and constant causing prolonged pharmacological actions.


Parenteral administration

  • Intramuscular

    • more rapid than subcutaneous

    • rate depends on blood supply to the site of injection

    • rate can be increased by increasing blood flow (example)


Pulmonary absorption

  • gaseous or volatile substances and aerosol can reach the absorptive site of the lung.

  • Highly available area of absorption

  • Pros: rapid, no first pass effect, directly reach desired site of action (asthma, COPD)

  • Cons: dose adjustment, complicated method of admin, irritating cpds.


Bioequivalence

  • Pharmaceutical equivalence (drawing)

  • Bioequivalence: PharEqui+ rate+ bioavialable drugs

  • Factors:

    • Physical property of the active ingredient: crystal form, particle size

    • Additive in theformulation: disintegrants

    • Procedure in drug production: force


An example of a generic product that could pass a bioequivalence test: Simvastatin (Parent form, n=18)


An example of a generic product that could pass a bioequivalence test: Ondansetron (n=14)


An example of a generic product that could pass a bioequivalence test: Clarithromycin (n=24)


Distribution

  • Drawing

  • distribution site: well-perfused organs, poor-perfused organs, plasma proteins

  • Well-perfused: heart, liver, kidney, brain

  • Poor-perfused: muscle, visceral organs, skin, fat


Distribution

  • Plasma proteins

    • Albumin: Weak acids

    • alpha-acid glycoprotein: Weak bases

  • Effects of plasma protein binding

    • Free fraction: active, excreted, metabolized

    • the more binding, the less active drug

    • the more binding, the less excreted and metabolized:

      “longer half-life”


Distribution

  • Effects of well distribution into the tissues

    • deep tissue as a drug reservoir

    • sustain released drug from the reservoir and redistributed to the site of its action

    • prolong pharmacologic actions


Distribution

CNS and CSF

  • Blood-Brain Barrier (BBB)

    • unique anatomical pattern of the vessels supplying the brain

    • only highly lipid soluble compounds can move across to the brain

    • infection of the meninges or brain: higher permeability of penicillins to the brain.


Distribution

Placental transfer

  • Simple diffusion

  • Lipid soluble drug, non-ionized species

  • first 3 mo. of pregnancy is very critical: “Organogensis”


Biotransformation

  • Why biotranformed? (Figure 5)

    • Normally, drugs have high lipid solubility therefore they will be reabsorbed when the filtrate reaching renal tubule by using tubular reabsorption process of the kidney.

    • Biotransformation changes the parent drug to metabolites which always have less lipid solubility (more hydrophilicity) property therefore they could be excreted from the body


Biotransformation

  • Biotransformation

    • to more polar cpds

    • to less active cpds

    • could be more potent (M-6-G) or more toxic (methanol to formaldehyde)


Biotransformation

  • Phase I and II Biotransformation

    • Phase I : Functionization, Functional group

    • Phase II: Biosynthetic, Molecule


Biotransformation

  • Phase I Reactions (Table 2)

    • Oxidation

    • Reduction

    • Hydrolysis


Biotransformation

  • Phase II Reactions (Table 3)

    • Glucuronidation

    • Acetylation

    • Gluthathione conjugation

    • Sulfate conjugation

    • Methylation


Biotransformation

  • Metabolite from conjugation reaction

    • Possibly excreted into bile acid to GI

    • Normal flora could metabolize the conjugate to the parent form and subsequently reabsorbed into the blood circulation. This pheonomenon is so-called “Enterohepatic circulation” which can prolong drug half-life.


Biotransformation

  • Site of biotransformation

    • Mostly taken place in the liver

    • Other drug metabolizing organs: kidney, GI, skin, lung

    • Hepatocyte (Drawing)


Biotransformation

The Liver:Site of biotransformation:

  • mostly enzymatic reaction by using the endoplasmic reticulum-dwelling enzymes.(Phase I), Cytosolic enzymes are mostly involved in the phase II Rxm.

  • Method of study phase I Rxm

    • Breaking liver cells

    • Centrifugation very rapidly

    • microsomes and microsomal enzymes


Biotransformation

  • Cytochrome P450 monooxygenase system (figure 6)

    • microsomal enzymes

    • Oxidation reaction using reducing agent (NADPH), O2

    • System requirement

      • Flavoprotein (NADPH-cytochrome P450 reductase, FMN+FAD) fuctions as an electron donor to cytochrome c.

      • Cytochrome P450 (CYP450)


Biotransformation

  • Steps in oxidative reactions (figure 6)

    • Step 1:Parent + CYP450

    • Step 2:Complex accepts electron from the oxidized flavoprotein

    • Step 3:Donored electron and oxygen forming a complex

    • Step 4: H2O and Metabolite formation


Biotransformation

  • CYP450 is a superfamily enzyme, many forms of them have been discovered (12 families).

  • Important CYP450 families in drug metabolism (Fig. 7)

    • CYP1 (1A2)

    • CYP2 (2E1, 2C, 2D6)

    • CYP3


Biotransformation

  • Factors affecting biotransformation

    • concurrent use of drugs: Induction and inhibition

    • genetic polymorphism

    • pollutant exposure from environment or industry

    • pathological status

    • age


Biotransformation

  • Enzyme induction

    • Drugs, industrial or environmental pollutants

    • increase metabolic rate of certain drugs leading to faster elimination of that drugs.

    • “autoinduction”

    • Table 4


Biotransformation

  • Enzyme induction

    • important inducers:

      • antiepileptic agents, glucocorticoids for CYP3A4

      • isoniazid, acetone, chronic use of alcohol for CYP2E1


Biotransformation

  • Enzyme inhibition:(drawing)

    • Competitive binding and reversible: Cimetidine, ketoconazole, macrolide metabolites

    • Suicidal inactivators: Secobarbital, norethindrone, ethinyl estradiol

    • Clinical significance: erythormycin and terfenadine or astemizole causing cardiac arrhythmia.


Biotransformation

  • Genetic polymorphism

    • Gene directs cellular functions through its products, protein.

    • Almost all enzymes are proteins so they have been directed by gene as well.

    • Drug-metabolizing enzymes:

      • Isoniazid: causing more neuropathy in caucaasians leading to identification of the first characterized pharmacogenetics.

      • due to the rate of N-acetylation: Slow and fast acetylators


Biotransformation

  • Pathologic conditions

    • Hepatitis

    • Cirrhosis due to chronic alcohol intake

    • Hypertensive pts recieving propranolol which lowers blood supply to the liver may lead to less biotransformation of the high extraction drugs such as lidocaine, propranolol, verapamil, amitryptyline


Excretion

  • Parent and metabolite

  • Hydrophilic compounds can be easily excreted.

  • Routes of drug excretion

    • Kidney

    • Biliary excretion

    • Milk

    • Pulmonary


Excretion

  • Renal excretion: Normal physiology

    • Glomerular filtration: Free fraction, filtration rate

    • Active tubular secretion: Energy dependent, carrier-mediated, saturable

      • Acids: penicillins and glucuronide conjugate (uric excretion)

      • Bases:choline, histamine and endogenous bases

    • Passive tubular reabsorption

      • non-ionized species back diffuse into blood circulation


Excretion

  • Clinical application of urine pH modification

    Drug toxicity

    • Weak base: Acidic urine pH enhances drug excretion by increasing numbers of inoized species by using ammonium chloride.

    • Weak cid: Basic urine pH enhances drug excretion by increasing numbers of inoized species by using sodium bicarbonate.


Excretion

  • Cationic, anionic and glucuronide conjugates can be excreted into bile acid and show enterohepatic cycle.


Clinical pharmacokinetics

  • Assumption: correlation between blood concentration and effects

  • MEC and MTC (figure 8)

  • Therapeutic range


Clinical pharmacokinetics

  • Order of reaction

    • zero order pharmacokinetics (Drawing): ethanol, high dose phenytoin and aspirin

    • first order pharmacokinetics: most drugs show first order pharmacokinetic fashion.


Clinical pharmacokinetics

  • Data: relationship between concentration and time (Drawing)

  • Compartmental model to explain above relationship (fig. 9)

  • Dosing and route of administration: IV bolus, IV infusion and oral ingestion


Clinical pharmacokinetics

  • Using first order:

    • IV bolus: concentration-time curve profile (fig 10)

    • explain equation number 1

    • which leads to these pharmacokinetic parameters: clearance, volume of distribution, half-life, Css, onset, duration, F


Clinical pharmacokinetics

  • Clearance

  • Vd

  • Half-life and Elimination constant

  • Onset

  • Duration

  • Steady state concentration

  • Absolute bioavialability


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