Pharmacokinetics

ผศ. มนุ�พั�ศ โลหิ�ตนุาวี�manupatl@nu.ac.thmanupatl@hotmail.com

OutlineIntroduction Physicochemical properties Absorption, Bioavialability, ro

utes of admistrationDistribution 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 (drawi

ng), with semipermeable property factors affecting drug across cellmembrane– cell membrane properties– physicochemical properties of drugs

Cell membranephysicochemical 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 co

mpounds– protein molecules function as rec

eptors 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 depend

s on pH (fig 2)– weak acid and weak base

Diffusion across the cell membrane

- Carrier mediated membrane trans port (drawing)

– lower conc to higher concentration a rea (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 stru

- cture related cpds, saturable Facillitated transport

– energy independent– structure specific, inhibited by stru

- cture related cpds, saturable

Saturable processDrawing - almost all protein mediated pro

cess in our body can occur this p rocess saturation not only trans

port system but also others suc -h as enzymatic reaction, drug li

gand binding and so on. because functional protein mole

cules are limited.

Drug absorption Parameters in drug absorption

– Rate constant of drug absorption (Ka)– Bioavialability (F)

Anatomical aspects affecting absorption para meters (Drawing)

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

– Liver (portal and hepatic vien, excretion via biliaryexcretion)

– cumulative degradation so called “First pass effect”

Drug absorptionFactors 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 Entera

l 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 cal culable dose

– Urgent situationCons

– Aseptic technic must be employed–Pain– limited self adminstration– More expensive

Enteral administration

Common use of enteraladministration– Oral administration– Sublingual administration

– Rectal administration

Enteral administration

- Concentrion time course of oral ad ministration (Drawing)

Rapid increase in plasma conc until reaching highest conc and subsequ

ent 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 t

he liver, high lipid solubility and high pot ency (little amount of absorbed molecule

s be able to show its pharmacological eff ects and relieve chest pain).

Enteral administration

Rectal adminstration– unconscious patients, pediatric patien

ts– 50% pass through the liver and 50% by

pass to the inferior vena cava– lower first pass effect than oral ingesti

on– 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, s

olubility in interstitial fluid High MW: Lymphatic pathway

Parenteral administration

Intravenous– precise dose and dosing interval– No absorption (F=1), all molecules reach blood ci

rculation– Pros: Calculable, promptly reach desired conc., Ir

ritating cpds have less effects than other routes– Cons: unretreatable, toxic conc, lipid solvent can

not be given by this route (hemolysis), closely monitored

Parenteral administration

Subcutaneous– - suitable for non irritatingcpds

– Rate is usually slow and co nstant 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 incre

asing blood flow (example)

Pulmonary absorption

gaseous or volatile substances and aeroso l can reach the absorptive site of the lung.

Highly available area of absorption Pros: rapid, no first pass effect, directly re

ach desired site of action (asthma, COPD) Cons: dose adjustment, complicated meth

od of admin, irritating cpds.

Bioequivalence Pharmaceutical equivalence (drawing) Bioequivalence: PharEqui+ rate+ bioav

ialable drugsFactors:

– 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)

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Time (hr)

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B

An example of a generic product that could pass a bioequivalence test:

Ondansetron (n=14)

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0 6 12 18 24

Time (hr)

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B

An example of a generic product that could pass a bioequivalence

test: Clarithromycin (n=24)

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500

1000

1500

2000

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Time (h)

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Klacid (A)

Claron (B)

Distribution

Drawing - distribution site: well perfused organ

- s, poor perfused organs, plasma proteins

- Well perfused: heart, liver, kidney, brain

- Poor perfused: muscle, visceral organ s, 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 meta

bolized:

“ -longer half life”

Distribution

Effects of well distribution into t he tissues

– deep tissue as a drug reservoir– sustain released drug from the res

ervoir and redistributed to the site of its action

– prolong pharmacologic actions

Distribution CNS and CSF CNS and CSF

- Blood Brain Barrier (BBB)– unique anatomical pattern of the vessel

s supplying the brain– only highly lipid soluble compounds can

move across to the brain– infection of the meninges or brain: highe

r permeability of penicillins to the brain.

Distribution

Placental transfer Placental transfer Simple diffusion -Lipid soluble drug, non ioniz

ed species first 3 mo. of pregnancy is v

ery critical: “Organogensis”

Biotransformation 5Why biotranformed? (Figure )

– Normally, drugs have high lipid solubility the refore they will be reabsorbed when the filtr

ate reaching renal tubule by using tubular re absorption process of the kidney.

– Biotransformation changes the parent drug t o metabolites which always have less lipid

solubility (more hydrophilicity) property therefore they could be excreted from the

body

BiotransformationBiotransformation

– to more polar cpds– to less active cpds– - -could be more potent (M 6 G

) or more toxic (methanol toformaldehyde)

Biotransformation

Phase I and II Biotransformation– Phase I : Functionizatio

n, Functional group– Phase II: Biosynthetic,Molecule

Biotransformation

Phase I Reactions (Table 2)–Oxidation–Reduction–Hydrolysis

Biotransformation

3Phase II Reactions (Table )–Glucuronidation–Acetylation– Gluthathione conjugation– Sulfate conjugation–Methylation

Biotransformation Metabolite from conjugation reaction

– Possibly excreted into bile acid to GI– Normal flora could metabolize the conju

gate to the parent form and subsequent ly reabsorbed into the blood circulation.

- This pheonomenon is so called “Entero hepatic circulation” which can prolon

-g drug half life.

Biotransformation Site of biotransformation

– Mostly taken place in the liver

– Other drug metabolizing org ans: kidney, GI, skin, lung

– Hepatocyte (Drawing)

Biotransformation

The Liver: Site of biotransformation: – mostly enzymatic reaction by using the e

- ndoplasmic reticulum dwelling enzymes. (Phase I), Cytosolic enzymes are mostly i

nvolved in the phase II Rxm.

– Method of study phase I Rxm Breaking liver cells Centrifugation very rapidly microsomes and microsomal enzymes

Biotransformation 450Cytochrome P monooxygenase sys

( 6 )– microsomal enzymes– Oxidation reaction using reducing agent (

NADPH), O2

– System requirement - 450Flavoprotein (NADPH cytochrome P reductas

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Biotransformation

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Biotransformation CYP450 is a superfamily enzyme, ma

ny forms of them have been discovere d (12 families).

Important CYP450 families in drug me tabolism (Fig. 7)

– CYP1 (1A2)– CYP2 (2E1, 2C, 2D6)– CYP3

Biotransformation

Factors affecting biotransformation– concurrent use of drugs: Induction an

d 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 dru gs leading to faster elimination of tha

t drugs.– “autoinduction”– Table 4

Biotransformation Enzyme induction

– important inducers: antiepileptic agents, glucocor

ticoids for CYP3A4 isoniazid, acetone, chronic us

e of alcohol for CYP2E1

Biotransformation Enzyme inhibition: (drawing)

– Competitive binding and reversible : C imetidine, ketoconazole, macrolide m

etabolites– Suicidal inactivators : Secobarbital, no

rethindrone, ethinyl estradiol– Clinical significance : erythormycin an

d terfenadine or astemizole causing c ardiac arrhythmia.

Biotransformation Genetic polymorphism Genetic polymorphism

– Gene directs cellular functions through it s products, protein.

– Almost all enzymes are proteins so they h ave been directed by gene as well.

– - Drug metabolizing enzymes: Isoniazid:causi ngmore neuropathy i ncaucaasi ans l eadi

ngto i denti fi cati onof the fi rst characteri ze

dpharmacogenetics. - dueto the rate of Nacetyl ati on: Slow and fastacetylators

Biotransformation

Pathologic conditions Pathologic conditions– Hepatitis– Cirrhosis due to chronic alcohol intake– Hypertensive pts recieving propranolol w

hich lowers blood supply to the liver may lead to less biotransformation of the high

extraction drugs such as lidocaine, propr anolol, 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, filtra tion rate

– Active tubular secretion: Energy depend - ent, carrier mediated, saturable

Acids:penicillinsandgl ucuroni de conj ugate (uri c excreti on) Bases:choline,hi stami ne andendogenous bases

– Passive tubular reabsorption - non ionized species back diffuse into bl

ood circulation

Excretion Clinical application of urine pH modifi

cation

Drug toxicity Drug toxicity– Weak base: Acidic urine pH enhances dru

g excretion by increasing numbers of inoi zed species by using ammonium chloride

.– Weak cid: Basic urine pH enhances drug

excretion by increasing numbers of inoiz ed species by using sodium bicarbonate.

Excretion

Cationic, anionic and glucu ronide conjugates can be exc

reted into bile acid and show ente rohepatic 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 p henytoin and aspirin

– first order pharmacokinetics: most drugs show first order ph

armacokinetic fashion.

Clinical pharmacokinetics

Data: relationship between conce ntration and time (Drawing)

Compartmental model to explain above relationship (fig. 9)

Dosing and route of administratio n: IV bolus, IV infusion and oral in

gestion

Clinical pharmacokinetics

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Clinical pharmacokinetics

ClearanceVd - Half life and Elimination constant

OnsetDuration Steady state concentration Absolute bioavialability