pharmacokinetics 2011
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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
Routes of Drug AdministrationRoutes of Drug Administration
1.1. EnteralEnteral♦ OralOral♦ SublingualSublingual♦ BuccalBuccal♦ RectalRectal
Routes of Drug AdministrationRoutes of Drug Administration
2. Parenteral2. Parenteral♦ IntradermalIntradermal♦ SubcutaneousSubcutaneous♦ IntramuscularIntramuscular♦ IntravenousIntravenous
Routes of Drug AdministrationRoutes of Drug Administration
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
Mechanisms of Passage Across Mechanisms of Passage Across MembranesMembranes
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
Mechanisms of Passage Across Mechanisms of Passage Across MembranesMembranes
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
Determinants of BioavalabilityDeterminants of Bioavalability
♦ 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
Determinants of BioavalabilityDeterminants of Bioavalability
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
Factors that Affect Distribution:Factors that Affect Distribution:
3. Permeability 3. Permeability and Perfusion and Perfusion of Membranesof Membranes
Factors that Affect Distribution:Factors that Affect Distribution:
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
Half- life (T½)Half- life (T½)
♦ 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
Half- life (T½)Half- life (T½)
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! “
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