advanced pharmacokinetics prof. dr. henny lucida, apt
TRANSCRIPT
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ADVANCED ADVANCED PHARMACOKINETICSPHARMACOKINETICS
Prof. Dr. Henny Lucida, AptProf. Dr. Henny Lucida, Apt
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TopicsTopics
• Drug Distribution Drug Distribution
• Drug Elimination and Clearance Drug Elimination and Clearance ConceptsConcepts
• Drug MetabolismDrug Metabolism
• Nonlinear PharmacokineticsNonlinear Pharmacokinetics
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ReferencesReferences
• Shargel, L and Yu, A, Applied Biopharmaceutics & Shargel, L and Yu, A, Applied Biopharmaceutics & Pharmacokinetics, 4Pharmacokinetics, 4thth ed., Appleton & Lange, 1999 ed., Appleton & Lange, 1999
• Gibaldi, M and Perrier, D, Pharmacokinetics, 2Gibaldi, M and Perrier, D, Pharmacokinetics, 2ndnd ed., ed., Marcel Dekker, 1982Marcel Dekker, 1982
• Banker, G.S. and Rhodes, C.T., Modern Banker, G.S. and Rhodes, C.T., Modern Pharmaceutics, 3Pharmaceutics, 3rdrd ed., Marcel Dekker, 1996 ed., Marcel Dekker, 1996
• Delgado,J.N. and Remers, W.A., Wilson and Delgado,J.N. and Remers, W.A., Wilson and Gisvold’s Textbook of Organic Medicinal and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 9Pharmaceutical Chemistry, 9thth ed., J.B. Lippincott, ed., J.B. Lippincott, 19911991
• Selected articlesSelected articles
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Drug DistributionDrug Distribution• Physiologic considerationPhysiologic consideration
Systemic circulation
Oral adm
GI tract
Im or sc
Tissuedepots
iv
Receptorsfor desiredeffects
drug drug drugDrug-drug
metabolitesDRUG
Serum albumin
drug Drug metab Drug-drug metabolites
LIVER GI tract
feces
kidney Receptorfor undesired
effeect
bile
duct
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Distribution patternDistribution pattern
Onced absorbed, drugs reached systemic Onced absorbed, drugs reached systemic circulation and were distributed throughout circulation and were distributed throughout the body, to receptor, other tissues (non the body, to receptor, other tissues (non receptor), eliminating organs, crossed the receptor), eliminating organs, crossed the placenta, secreted in milk (ASI) and in fat placenta, secreted in milk (ASI) and in fat tissuestissues
Body fluids (totally 42 L for 70 kg subject BW)Body fluids (totally 42 L for 70 kg subject BW)1.1. The vascular fluid (blood, The vascular fluid (blood, ++ 5L) 5L)2.2. The extracellular fluid (The extracellular fluid (++ 15 L incl plasma 3L) 15 L incl plasma 3L)3.3. The intracellular fluid The intracellular fluid
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Physicochemical factorsPhysicochemical factors
Determined distr pattern of drugs, incl:Determined distr pattern of drugs, incl:• MW (low MW & water soluble drugs were MW (low MW & water soluble drugs were
uniformly distributed throughout the uniformly distributed throughout the bodywater)bodywater)
• Solubility Solubility • pKa (only molecular form passed the pKa (only molecular form passed the
physiological membrane)physiological membrane)• Partition coefficient (lipid soluble drugs tend to Partition coefficient (lipid soluble drugs tend to
accumulate in fat tissues)accumulate in fat tissues)• Affinity to plasma protein (high affinity drugs, Affinity to plasma protein (high affinity drugs,
stay largely within the vascular system)stay largely within the vascular system)
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Physiological factorsPhysiological factors
• Membrane permeability (highly permeable: renal Membrane permeability (highly permeable: renal and hepatic capillaries, impermeable: brain and hepatic capillaries, impermeable: brain capillaries; blood-brain barrier)capillaries; blood-brain barrier)
• Blood perfusion rate (kidneys>liver>heart> Blood perfusion rate (kidneys>liver>heart> brain>fat>muscle> skin>bone)brain>fat>muscle> skin>bone)
Exp: thiopental gets into the brain faster than Exp: thiopental gets into the brain faster than muscle, whereas penicillin was viceversamuscle, whereas penicillin was viceversa
Thiopental is partly ionized and passes both organs Thiopental is partly ionized and passes both organs easily. Perfusion limits the transport thus it can easily. Perfusion limits the transport thus it can transfer to the brain more quickly.transfer to the brain more quickly.
Penicillin, being quite polar and thus slowly Penicillin, being quite polar and thus slowly permeable. Permeability limits transfer thus it permeable. Permeability limits transfer thus it gets muscle easily (brain is impermeable)gets muscle easily (brain is impermeable)
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Distribution processDistribution process
• Passive diffusion (Fick’s law of Passive diffusion (Fick’s law of diffusion)diffusion)
• Hydrostatic pressure (a pressure Hydrostatic pressure (a pressure gradient between the arterial end of gradient between the arterial end of the capillaries entering the tissue the capillaries entering the tissue and the venous capillaries leaving and the venous capillaries leaving the tissue).Responsible for the tissue).Responsible for penetration of water-soluble drugs.penetration of water-soluble drugs.
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Perfusion or flow limited Perfusion or flow limited distr.distr.
• If a drug difuses rapidly across the If a drug difuses rapidly across the membrane so that blood flow is the membrane so that blood flow is the rate limiting step (slower)rate limiting step (slower)
exp: thiopental, transport to the exp: thiopental, transport to the brainbrain
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Diffusion or permeability limited Diffusion or permeability limited distr.distr.
• If drug distribution is limited by the If drug distribution is limited by the slow diffusion of drug across the slow diffusion of drug across the membrane in the tissuemembrane in the tissue
exp: penicillin, diffused very slowly exp: penicillin, diffused very slowly due to its polaritydue to its polarity
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Two compartment open Two compartment open modelmodel
Tissue compartment
Central compartment (plasma)
k12 k21
Absorption
k10 Elimination
Distribution
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Apparent volume of Apparent volume of distributiondistribution• Lack of true volume characteristics (due to unknown Lack of true volume characteristics (due to unknown
tissue volume).tissue volume).Vd app of some drugs exceed total body water (see Vd app of some drugs exceed total body water (see Table 1).Table 1).
• Defined as the hypothetical volume relating the drug Defined as the hypothetical volume relating the drug plasma concentration to the weight of drug in the plasma concentration to the weight of drug in the bodybody
• A useful indicator of the type of distribution pattern, A useful indicator of the type of distribution pattern, exp: V= 3-5 L (in an adult) exp: V= 3-5 L (in an adult) the drug remain the drug remain largely within the vascular system; V= 30 – 50 L largely within the vascular system; V= 30 – 50 L the drug is distributed throughout the body water; V the drug is distributed throughout the body water; V >>> total body water >>> total body water drugs are concentrated in one drugs are concentrated in one or more tissues (highly lipid soluble drugs distribute or more tissues (highly lipid soluble drugs distribute into fat tissue, digoxin is extensively bound by into fat tissue, digoxin is extensively bound by myocard protein)myocard protein)
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Tabel 1. Apparent Vd of some Tabel 1. Apparent Vd of some drugsdrugs
DrugDrug Liters/kgLiters/kg Liter/70 kgLiter/70 kg
ChloroquineChloroquine 94 – 25094 – 250 6600 – 175006600 – 17500
NortriptylineNortriptyline 2121 15001500
DigoxinDigoxin 77 500500
LidocaineLidocaine 1.71.7 120120
TheophyllineTheophylline 0.50.5 3535
TolbutamideTolbutamide 0.110.11 88
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Basic equationsBasic equations
• CCpp = D = DBB/V/Vdd
• Distrib. Half life: Distrib. Half life:
Q=blood flow to the organ,V=volume of Q=blood flow to the organ,V=volume of the organ & R=ratio of drug conc in tissue the organ & R=ratio of drug conc in tissue to conc in bloodto conc in blood
• TT1/21/2 elimination elimination VdVd
CL = k VCL = k Vdd
TT1/21/2 = 0.693 V = 0.693 Vdd/CL/CL
VR
Qkd
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Calculation of Vd app.Calculation of Vd app.
• VVappapp = D = DBB/C/Cpp
• DDBB = V = VppCCpp + V + VttCCtt
• VVappapp = V = Vpp + V + Vtt [f [fuu/f/futut], if ], if ffu u and fand fut ut are both unity, are both unity, thenthen
DDBB/C/Cpp = V = Vpp + V + Vtt
• Estimation of VEstimation of Vappapp
0
app C
DoseV
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Protein BindingProtein Binding
Major proteins to which dugs bind in plasma: Major proteins to which dugs bind in plasma: albumin (acidic drugs), albumin (acidic drugs), 1-acid glycoprotein 1-acid glycoprotein (basic drugs), lipoproteins(basic drugs), lipoproteins
Significance: Significance: • only free drug is able to cross membrane, the only free drug is able to cross membrane, the
bound drug could serve as reservationbound drug could serve as reservation• Possibility of drug interaction by binding Possibility of drug interaction by binding
displacementdisplacement• Free drug conc was also determined by Free drug conc was also determined by
patophysiological conditions relating with patophysiological conditions relating with changes in the amount of protein in the bodychanges in the amount of protein in the body
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Drug-Protein BindingDrug-Protein Binding
• ReversibleReversible
hydrogen or van der walls bound hydrogen or van der walls bound (weak)(weak)
• IrreversibleIrreversible
cause toxicity such as hepatotoxicity cause toxicity such as hepatotoxicity due to binding of acetaminophen to due to binding of acetaminophen to liver proteinliver protein
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Effect of reversible protein binding on Effect of reversible protein binding on drug distribution & eliminationdrug distribution & elimination
Tissues
Plasma
Kidney Liver
Drug-Receptor
Receptor + Drug
Protein + Drug
Drug-Protein
Carrier+Drug
Drug-Carrier
Drug+Enzymes
Metabolites
Clinical response
ExcretionIn urine
Active renalsecretion
Excretion In urine
ExcretionIn bile
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Table: Influence of protein binding on t1/2 & Table: Influence of protein binding on t1/2 & CLCLRR
DrugDrug % Bound% Bound T1/2 (hr)T1/2 (hr) CLCLRR(mL/min/(mL/min/1.73m1.73m22))
CeftriaxoneCeftriaxone 9696 8.08.0 1010CefoperazonCefoperazonee
9090 1.81.8 1919
CefotetanCefotetan 8585 3.33.3 2828CeforanideCeforanide 8181 3.03.0 4444CefazolinCefazolin 7070 1.71.7 5656MoxalactamMoxalactam 5252 2.32.3 6464CefsulodinCefsulodin 2626 1.51.5 9090CeftazidimeCeftazidime 2222 1.91.9 8585CephaloridinCephaloridinee
2121 1.51.5 125125
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Methods for studying drug-Methods for studying drug-protein bindingprotein binding
• Equilibrium dialysisEquilibrium dialysis
• Dynamic dialysisDynamic dialysis
• UltrafiltrationUltrafiltration
• Gel ChromatographyGel Chromatography
• SpectrophotometrySpectrophotometry
• ElectrophoresisElectrophoresis
• Circulatory dichroismCirculatory dichroism
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Clinical Significance Clinical Significance
Factors that decrease plasma protein Factors that decrease plasma protein conc:conc:
• Liver disease: decrease protein Liver disease: decrease protein synthesissynthesis
• Trauma, surgery: increased protein Trauma, surgery: increased protein catabolismcatabolism
• Burns: Distribution of albumin into Burns: Distribution of albumin into extravascular spaceextravascular space
• Renal disease: Excessive elimination of Renal disease: Excessive elimination of proteinprotein