Pharmacokinetics 2011

PharmacokineticsPharmacokinetics20112011

Maria Luisa D. Delacruz. MDMaria Luisa D. Delacruz. MDDLS-HSI College of Medicine DLS-HSI College of Medicine Department of PharmacologyDepartment of Pharmacology

PharmacokineticsPharmacokinetics

““What the body does to the drug?”What the body does to the drug?”

““How the body handles the drug?”How the body handles the drug?”

Pharmacokinetic ProcessesPharmacokinetic Processes

♦ AbsorptionAbsorption♦ DistributionDistribution♦ Metabolism / BiotransformationMetabolism / Biotransformation♦ ExcretionExcretion

Routes of Drug AdministrationRoutes of Drug Administration

1.1. EnteralEnteral2.2. ParenteralParenteral3.3. TopicalTopical


1.1. EnteralEnteral♦ OralOral♦ SublingualSublingual♦ BuccalBuccal♦ RectalRectal


2. Parenteral2. Parenteral♦ IntradermalIntradermal♦ SubcutaneousSubcutaneous♦ IntramuscularIntramuscular♦ IntravenousIntravenous


3.Topical3.Topical♦ DermalDermal♦ InhalationalInhalational♦ Mucous membraneMucous membrane

NasalNasal Ophthalmic/OticOphthalmic/Otic VaginalVaginal

Mechanisms of Drug Passage Across Mechanisms of Drug Passage Across MembranesMembranes

1.1. Passive DiffusionPassive Diffusion2.2. Facilitated DiffusionFacilitated Diffusion3. Active Transport3. Active Transport4. Pinocytosis4. Pinocytosis

Mechanisms of Passage Across Mechanisms of Passage Across MembranesMembranes

PASSIVE DIFFUSIONPASSIVE DIFFUSION

♦ higher conc higher conc lower conc lower conc♦ driving force – difference in drug concdriving force – difference in drug conc♦ utilized by majority of drugsutilized by majority of drugs

Passive Diffusion

Mechanisms of Passage Across MembranesMechanisms of Passage Across Membranes

Facilitated DiffusionFacilitated Diffusion♦ carrier-mediated transport process carrier-mediated transport process ♦ does not require energydoes not require energy♦ carrier enhances movement of the drug down carrier enhances movement of the drug down an electrochemical gradient an electrochemical gradient e.g. GLUT 4 enhances the permeation of glucose e.g. GLUT 4 enhances the permeation of glucose

across a muscle cell membrane across a muscle cell membrane


ACTIVE TRANSPORT ACTIVE TRANSPORT

♦ requires carrierrequires carrier♦ energy consumingenergy consuming♦ against a concentration gradientagainst a concentration gradient♦ saturabilitysaturability♦ selectivityselectivity♦ competitive inhibition by competitive inhibition by co-transported compoundsco-transported compounds


PINOCYTOSIS♦ folding over the part of the cell membrane♦ formation of small vesicle♦ molecules of extracellular

contents are trapped

Factors that Affect the Drug Passage Factors that Affect the Drug Passage Across Membranes Across Membranes

1. molecular size and shape1. molecular size and shape2. degree of ionization2. degree of ionization3. relative lipid solubility of its ionized 3. relative lipid solubility of its ionized

and nonionized formsand nonionized forms4. binding to serum and tissue proteins 4. binding to serum and tissue proteins

ABSORPTIONABSORPTION

♦ is the movement of a drug from its site is the movement of a drug from its site of administration to the systemic of administration to the systemic circulation and the extent to which this circulation and the extent to which this occursoccurs

ABSORPTIONABSORPTION

For an orally administered drug, Absorption For an orally administered drug, Absorption depends on:depends on:

1.1. disintegrationdisintegration2.2. dissolutiondissolution3.3. diffusiondiffusion

Factors that Affect the Rate and Extent Factors that Affect the Rate and Extent of Drug Absorptionof Drug Absorption

1.1. Dosage form / Drug formulationDosage form / Drug formulation2.2. Physicochemical Properties of the DrugPhysicochemical Properties of the Drug

♦ molecular weightmolecular weight♦ pHpH♦ lipophilic vs hydrophiliclipophilic vs hydrophilic

* Partition coefficient* Partition coefficient

♦ most drugs are weak acids or bases that most drugs are weak acids or bases that are present in solution as both the are present in solution as both the nonionized and ionized forms nonionized and ionized forms

♦ nonionized substances are usually more nonionized substances are usually more lipid-soluble and can diffuse readily lipid-soluble and can diffuse readily across the cell membraneacross the cell membrane

♦ ionized molecules have low lipid solubility ionized molecules have low lipid solubility and are unable to penetrate the lipid and are unable to penetrate the lipid membranemembrane

Factors that Affect the Rate and Extent Factors that Affect the Rate and Extent of Drug Absorptionof Drug Absorption

3. Physiologic variables3. Physiologic variables♦ gastric motilitygastric motility♦ pH at the absorptive sitepH at the absorptive site♦ area of absorbing surfacearea of absorbing surface♦ mesentric blood flowmesentric blood flow♦ presystemic elimination / first passpresystemic elimination / first pass

Acidic pHAcidic pHweak acid – more unioinized – more weak acid – more unioinized – more lipid soluble lipid soluble weak base – less unionized – less lipid weak base – less unionized – less lipid

solublesolubleAlkaline pHAlkaline pH

weak acid – less unionized – less lipid solubleweak acid – less unionized – less lipid soluble

weak base – more unionized – more lipidweak base – more unionized – more lipid solublesoluble

pH at Absorptive site

BIOAVAILABILITYBIOAVAILABILITY

♦ measures the rate and extent by measures the rate and extent by which a drug reaches systemic which a drug reaches systemic circulationcirculation

♦ fraction of unchanged drug that fraction of unchanged drug that reaches systemic circulationreaches systemic circulation

Factors that Affect BioavailabilityFactors that Affect Bioavailability1. Biopharmaceutical factors1. Biopharmaceutical factors

♦ Dosage formDosage form♦ Physicochemical propertiesPhysicochemical properties

2. Physiologic factors2. Physiologic factors♦ Gastric motilityGastric motility♦ Presystemic metabolismPresystemic metabolism

3. GIT contents – Food, drugs, fluid3. GIT contents – Food, drugs, fluid4. Disease states4. Disease states

Determinants of BioavalabilityDeterminants of Bioavalability

1. Plasma data


♦ AUC is the most reliable AUC is the most reliable measure of measure of bioavailability. bioavailability.

♦ It is directly proportional It is directly proportional to the total amount of to the total amount of unchanged drug that unchanged drug that reaches the systemic reaches the systemic circulationcirculation


2. Urine data2. Urine data♦ maximum urinary excretion ratemaximum urinary excretion rate♦ time for maximum excretion rate time for maximum excretion rate ♦ cumulative amount of drug excreted in thecumulative amount of drug excreted in the urineurine3. Pharmacologic effect3. Pharmacologic effect

BioavailabilityBioavailability

Bioequivalence:Bioequivalence:♦ when two related drugs show when two related drugs show

comparable bioavailability comparable bioavailability

Therapeutic Equivalence:Therapeutic Equivalence:♦ when two similar drugs have when two similar drugs have

comparable efficacy and safetycomparable efficacy and safety

Routes of Administration, Bioavailability, and General Routes of Administration, Bioavailability, and General CharacteristicsCharacteristics

RouteBioavailability

(%)Characteristics

Intravenous (IV) 100 (by definition) most rapid onset

Intramuscular (IM) 75 to ≤ 100 large volumes often feasible; may be painful

Subcutaneous (SC) 75 to ≤ 100 smaller volumes than IM; may be painful; slower onset than IV or IM

Oral (PO) 5 to < 100 most convenient; first-pass effect may be significant

Rectal (PR) 30 to < 100 less first-pass effect than oral

Transdermal 80 to ≤ 100 usually very slow absorption; used for lack of first-pass effect; prolonged duration of action

DistributionDistribution

♦ process by which a drug process by which a drug reversibly leaves the systemic reversibly leaves the systemic circulation and enters the circulation and enters the interstitial space and/or the interstitial space and/or the cells of the tissuescells of the tissues

♦ once in the blood stream, the once in the blood stream, the drug is distributed to the drug is distributed to the different tissuesdifferent tissues

DISTRIBUTIONDISTRIBUTION

Factors that Influence Drug DistributionFactors that Influence Drug Distribution

1.1. Plasma Protein BindingPlasma Protein Binding2.2. Cardiac Output an Regional Cardiac Output an Regional

Blood FlowBlood Flow3.3. Permeability and Perfusion of Permeability and Perfusion of

MembranesMembranes4.4. DiseasesDiseases

Factors that Affect Distribution:Factors that Affect Distribution:1. Plasma protein binding1. Plasma protein binding

♦ drugs bound to drugs bound to proteins are not proteins are not readily distributed readily distributed

and are inactiveand are inactive♦ high protein binding high protein binding

prolongs onset and prolongs onset and duration of action duration of action

Factors that Affect Drug DistributionFactors that Affect Drug Distribution

Plasma protein bindingPlasma protein binding♦ weakly acidic drugs – albuminsweakly acidic drugs – albumins♦ weakly basic drugs – weakly basic drugs – -1-acid -1-acid

glycoproteinsglycoproteins♦ free, unbound drug is the active form free, unbound drug is the active form

of the drugof the drug

Factors that Affect Distribution:Factors that Affect Distribution:

2. Cardiac output and 2. Cardiac output and blood flow to the blood flow to the tissuestissues

♦ highly vascular organs highly vascular organs receive more of the receive more of the drugsdrugs


3. Permeability 3. Permeability and Perfusion and Perfusion of Membranesof Membranes


Natural barriers Natural barriers ♦ Blood brain barrierBlood brain barrier♦ Placental barrierPlacental barrier♦ Blood-ocular barrierBlood-ocular barrier

♦ Prevent distribution of drug to areas Prevent distribution of drug to areas where their effects may be dangerouswhere their effects may be dangerous

Blood brain barrier

Placental barrier

Factors that Affect Drug DistributionFactors that Affect Drug Distribution

4. Diseases4. Diseases♦ renal, cardiac failurerenal, cardiac failure♦ plasma albumin conc: plasma albumin conc: ↓↓ in malnutrition, in malnutrition,

hepatic and renal diseaseshepatic and renal diseases♦ alpha-1-acid glycoprotein conc: alpha-1-acid glycoprotein conc: ↓↓ in in

pregnancy and post MIpregnancy and post MI

Volume of DistributionVolume of Distribution

♦ the volume of fluid to which a drug is the volume of fluid to which a drug is distributeddistributed

♦ drugs with large volume of distribution drugs with large volume of distribution will have a longer half-life and duration will have a longer half-life and duration of actionof action

Volume of DistributionVolume of Distribution

amount of drug administered

initial drug concentrationVD =

♦ relates the amount of a given drug in the body to the concentration of the drug in the blood

Metabolism / BiotransformationMetabolism / Biotransformation

♦ process by which a drug is altered chemically process by which a drug is altered chemically into another compound called “metabolites” into another compound called “metabolites” which may be more active or less active than the which may be more active or less active than the parent drugparent drug

♦ primarily occurs in the liverprimarily occurs in the liver♦ can also occur in the stomach, small intestines, can also occur in the stomach, small intestines,

plasma, kidney, lung, skin, other tissuesplasma, kidney, lung, skin, other tissues

Metabolism / BiotransformationMetabolism / Biotransformation

Two Phases:Two Phases:1. Phase I reaction1. Phase I reaction

♦ oxidation, hydrolysis, reductionoxidation, hydrolysis, reduction♦ mediated by cytochrome P450 (drug mediated by cytochrome P450 (drug

metabolizing enzymesmetabolizing enzymes) )

2. Phase II reaction2. Phase II reaction♦glucuronidation, sulfation, glutathione glucuronidation, sulfation, glutathione

conjugation, n-acetylation, methylationconjugation, n-acetylation, methylation

MetabolismMetabolism

Significance:Significance:♦ defensive mechanismdefensive mechanism♦ increases polarity of drug moleculesincreases polarity of drug molecules

restricts penetration thru cellular restricts penetration thru cellular membranemembrane

reduces distributionreduces distribution promotes eliminationpromotes elimination

Factors Affecting Drug MetabolismFactors Affecting Drug Metabolism

1. Non – Genetic1. Non – Genetic♦ AgeAge♦ SexSex♦ Liver size / functionLiver size / function♦ Diet / NutritionDiet / Nutrition♦ EnvironmentalEnvironmental

2. Genetic2. Genetic

Factors Affecting Drug MetabolismFactors Affecting Drug Metabolism

2. Genetic2. Genetice.g.e.g.

Acetylation – slow and fastAcetylation – slow and fast

Oxidation – poor and extensiveOxidation – poor and extensive

ExcretionExcretion

♦ process by which a drug or its process by which a drug or its metabolites is eliminated from the bodymetabolites is eliminated from the body

♦ main organ of elimination is the main organ of elimination is the kidneyskidneys

♦ other organ of excretion include the other organ of excretion include the biliary system, GIT, skin and lungsbiliary system, GIT, skin and lungs

Renal ExcretionRenal Excretion

♦ Glomerular Glomerular filtrationfiltration

♦ Tubular Tubular secretionsecretion

Half- life (T½)Half- life (T½)

♦ time required to decrease the concentration time required to decrease the concentration of the drug in the plasma by 50%of the drug in the plasma by 50%

♦ often used to determine frequency of often used to determine frequency of administrationadministration

♦ determines the time to attain steady-state determines the time to attain steady-state concentration concentration


♦ Drug needs about 4-5 half lives to be Drug needs about 4-5 half lives to be completely eliminated from the bodycompletely eliminated from the bodyE.g. Paracetamol (ACET) 500 mg half-life 4 hrsE.g. Paracetamol (ACET) 500 mg half-life 4 hrs

after 1after 1st st 4 hrs = 250 mg4 hrs = 250 mgafter 2after 2ndnd 4 hrs = 125 mg 4 hrs = 125 mgafter 3after 3rdrd 4 hrs = 62.5 mg 4 hrs = 62.5 mgafter 4after 4thth 4 hrs = 31.25 4 hrs = 31.25after 5after 5thth 4 hrs = 15. 635 4 hrs = 15. 635


T ½ = 0.7 x Vd Cl

Where:Vd = volume of distributionCl = clearance

Steady StateSteady State

♦ the point where rate of drug availability the point where rate of drug availability equals rate of eliminationequals rate of elimination

♦ constant drug concentrationconstant drug concentration♦ point where expect maximum drug effectpoint where expect maximum drug effect♦ usually attained after 4-5 half livesusually attained after 4-5 half lives

Steady StateSteady State

ClearanceClearance

♦ the measure of the ability of the body to the measure of the ability of the body to eliminate the drugeliminate the drug

♦ the sum of hepatic metabolism and renal the sum of hepatic metabolism and renal excretionexcretion

Kinetic OrderKinetic Order

1. Zero order1. Zero order

2. First order2. First order

Zero Order Zero Order

♦ constant constant ♦ independent of the amount of independent of the amount of

drugdrug♦ linearlinear♦ active transportactive transport

First OrderFirst Order

♦ not uniformnot uniform♦ proportional to the amount of drugproportional to the amount of drug♦ CurvilinearCurvilinear♦ passive diffusionpassive diffusion

Elimination of DrugsElimination of Drugs

Order of Elimination

1. First Order 2. Zero Order

Time after Drug Administration

Drug in

Body

(mg)

Amount of Drug Eliminated

Fraction of Drug Eliminated

0 1000 ---- ----

1 850 150 0.15

2 700 150 0.18

3 550 150 0.21

4 400 150 0.27

5 250 150 0.38

6 100 150 0.60

Zero order EliminationZero order Elimination

First order EliminationFirst order Elimination

Time after Drug Administration

Drug in Body

(mg)

Amount of Drug

Eliminated

Fraction of Drug

Eliminated

0 1000 ---- ----

1 850 150 0.15

2 723 127 0.15

3 614 109 0.15

4 522 92 0.15

5 444 78 0.15

6 377 67 0.15

““The gift of The gift of true true

friendship is friendship is that it takes that it takes

us by the us by the hand and hand and

reminds us reminds us we are not we are not alone in the alone in the journey! “journey! “

Documents

Pharmacokinetics 2011