ADVANCED ADVANCED PHARMACOKINETICSPHARMACOKINETICS

Prof. Dr. Henny Lucida, AptProf. Dr. Henny Lucida, Apt

TopicsTopics

• Drug Distribution Drug Distribution

• Drug Elimination and Clearance Drug Elimination and Clearance ConceptsConcepts

• Drug MetabolismDrug Metabolism

• Nonlinear PharmacokineticsNonlinear Pharmacokinetics

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

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

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

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)

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)

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.

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

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

Two compartment open Two compartment open modelmodel

Tissue compartment

Central compartment (plasma)

k12 k21

Absorption

k10 Elimination

Distribution

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)

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

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

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

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

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

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

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

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

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