Pharmacok inetics

ผศ .

มนุพัศ โลหิต นาวี [email protected].

th manupatl@hotma il.com

Outline



Introduction



Physicochemical properties

 

Absorption, Bioavialability, routes 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

8.00

6.00

4.00

2.00

0.00

0 4 8 12 Time (hr) 16 20 24 A B

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

60 A B 40 20 0 0 6 12 Time (hr) 18 24

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

2500 2000 Klacid (A) Claron (B) 1500 1000 500 0 0 4 8 12 Time (h) 16 20 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 body

be excreted

from the

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), O 2

– 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: H 2 O 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 metabolites : Cimetidine, ketoconazole, macrolide

– –

Suicidal inactivators : Secobarbital, norethindrone, ethinyl estradiol Clinical significance cardiac arrhythmia.

: erythormycin and terfenadine or astemizole causing



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

excretion by increasing numbers of inoized species by using enhances drug

ammonium chloride.

Weak cid: Basic urine pH

excretion by increasing numbers of inoized species by using enhances drug

sodium bicarbonate.

Excretion



Cationic, anionic and glucuronide conjugates

excreted into bile acid and show enterohepatic cycle.

can be

Clinical pharmacokinetics



Assumption:

between blood concentration and effects correlation



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