Chapter 1 Pharmacokinetics 药物代谢动力学 §PK process in the body §Kinetic processes

Chapter 1Chapter 1

PharmacokineticsPharmacokinetics药物代谢动力学药物代谢动力学

PK process in the bodyPK process in the body

Kinetic processesKinetic processes

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

1. Overview1. Overview

2. 2. Transport of Drug in the BodyTransport of Drug in the Body

3. Pharmacokinetic Processes of the Drug3. Pharmacokinetic Processes of the Drug in the Bodyin the Body

OverviewOverview

Mechanisms of drug permeationMechanisms of drug permeation

A. aqueous channels in the intercellular junctions

B.B. lipid cell lipid cell membranesmembranes

C.C. carriers carriers (transporters) (transporters) (into or out of (into or out of cells)cells)

D.D. endocytosis endocytosis

exocytosisexocytosis

2.2. Transport of Drug in the Body Transport of Drug in the Body

2.1 Transmembrane Transport of Drugs2.1 Transmembrane Transport of Drugs

(1) Non-carrier transport(1) Non-carrier transport

Simple diffusionSimple diffusion （（简单扩散简单扩散 // 单纯扩散单纯扩散）） FiltrationFiltration （（滤过滤过））


Part APart A Pharmacokinetic Pharmacokinetic ProcessesProcesses

Characteristics of simple diffusionCharacteristics of simple diffusion

Not involving specific carriersNot involving specific carriers

Energy-independentEnergy-independent

No saturabilityNo saturability

No competition with other drugsNo competition with other drugs

Concentration gradient (down-hill)Concentration gradient (down-hill)

(2) Carrier-mediated transport (2) Carrier-mediated transport

a. Active transporta. Active transport

Characteristics of active transportCharacteristics of active transport Involving specific carrier (Involving specific carrier (transportertransporter)) Energy-dependentEnergy-dependent SaturabilitySaturability Competition at same carrierCompetition at same carrier Moving against concentration gradient (up-hill)Moving against concentration gradient (up-hill)


b. Facilitated diffusionb. Facilitated diffusion （（易化扩散易化扩散）） ((transporter-mediated diffusiontransporter-mediated diffusion))

Involving specific carriers (Involving specific carriers (transportertransporter) ) Energy-independentEnergy-independent SaturabilitySaturability Competition with other drugsCompetition with other drugs Concentration gradient (down-hill)Concentration gradient (down-hill)

(3) Membrane moving transport(3) Membrane moving transport （膜动转运）（膜动转运） Endocytosis/exocytosisEndocytosis/exocytosis （入胞（入胞 // 出胞）出胞）


A. Simple diffusionA. Simple diffusion


Most drugs are weak acids or bases.

Their diffusion passing through cell membrane depends the lipid-soluble state (un-ionized form)

Determinants of simple diffusionDeterminants of simple diffusion

For most drugs of small molecules (usually aFor most drugs of small molecules (usually are weak acids or weak bases):re weak acids or weak bases):

Lipid-soluble or un-ionized formsLipid-soluble or un-ionized forms

pKa pKa of the drug andof the drug and pHpH of the body fluidof the body fluid

TheThe pKapKa is the pH at which the concentrations of this the pH at which the concentrations of the ionized and un-ionized forms are equal.e ionized and un-ionized forms are equal.


Henderson-Hasselbalch equationHenderson-Hasselbalch equation

Weak acid drugs: Weak acid drugs: ppH - H - ppKa = log ( [AKa = log ( [A--] / [HA] )] / [HA] ) ppKa - Ka - ppH = log ( [HA] / [AH = log ( [HA] / [A--] )] )

Weak base drugs:Weak base drugs: ppKa - Ka - ppH = log ( [BHH = log ( [BH++] / [B] )] / [B] ) ppH - H - ppKa = log ( [B] / [BHKa = log ( [B] / [BH++] )] )



ppHH ppKaKaun-ionized un-ionized

formformlipid-lipid-solublesoluble

Simple Simple diffusiondiffusion

Weak Weak acidsacids

Weak Weak basesbases

And / orAnd / or

And / orAnd / or

And / orAnd / or

And / orAnd / or

ImplicationsImplications

Absorption: Absorption: Stomach/intestineStomach/intestine

Distribution: Distribution: Plasma/intracellularPlasma/intracellular

Excretion: Excretion: Urine pH/weak acid or baseUrine pH/weak acid or base


Weak acidWeak acid

Weak baseWeak base

Trapping of a weak base (methamphetamine) in the Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the bloodurine when the urine is more acidic than the blood

Three types of functional membrane proteins.Three types of functional membrane proteins.

B. Carrier (transporter)-mediated B. Carrier (transporter)-mediated transporttransport

Models of transmembrane transport across the lipid bilayerModels of transmembrane transport across the lipid bilayer

Transporter superfamilyTransporter superfamily （转运体超家族）（转运体超家族）

根据不断增加的转运体成员，人类基因命名委员会对转运体作了标准化命名，分为两大类：

ATP-ATP- 结合盒转运体结合盒转运体（ ATP-binding cassette [ABCABC] transporters ）— mediating active transportactive transport

1212 次跨膜结构次跨膜结构（（ P-gpP-gp 、、 MRP4MRP4 、、 MRP5MRP5 ）） 1717 次跨膜结构次跨膜结构（（ MRP1MRP1 、、 MRP2MRP2 、、 MRP3MRP3 、、 MRP6MRP6 ）） 66 次跨膜结构次跨膜结构（（ BCRP, BCRP, 组成二聚体发挥作用组成二聚体发挥作用））

溶质载体转运体溶质载体转运体（ solute carrier [SLCSLC] transporters ） — mediating facilitated diffusionfacilitated diffusion

有机阴离子转运体（有机阴离子转运体（ organic anion transporter, OATorganic anion transporter, OAT ）家族）家族有机阳离子转运体（有机阳离子转运体（ organic cation transporter, OCTorganic cation transporter, OCT ）家族）家族多肽转运体（多肽转运体（ peptide transporter, PEPTpeptide transporter, PEPT ））核苷转运体（核苷转运体（ nucleoside transporter, NTnucleoside transporter, NT ））

Primary active transportPrimary active transport

((P-glycoprotein, multidrug P-glycoprotein, multidrug resistance protein [MRP] )resistance protein [MRP] )

Secondary active trSecondary active transport ansport

+ +

facilitated diffusionfacilitated diffusion

(organic anion / cai(organic anion / caion transporters)on transporters)

Transporters of drugs in PK processesTransporters of drugs in PK processes

2.2 Free and Bound Forms2.2 Free and Bound Forms

Plasma protein bindingPlasma protein binding

Tissue / organ affinityTissue / organ affinity


3.3. Fate of the drug in the body Fate of the drug in the body

AbsorptionAbsorption DistributionDistribution MetabolismMetabolism (Biotransformation)(Biotransformation)

ExcretionExcretion －－ ADMEADME


ADME

3.1 Absorption3.1 AbsorptionAbsorption is the transfer of a drug from its site of aAbsorption is the transfer of a drug from its site of a

dministration to the blood stream.dministration to the blood stream.

Gastrointestinal tractGastrointestinal tract Parenteral injection - Parenteral injection - i.m., s.c.i.m., s.c. InhalationInhalation Transdermal Transdermal


(1) Gastrointestinal tract(1) Gastrointestinal tract

Route:Route: OralOral SublingualSublingual RectalRectal

Absorption sites:Absorption sites: Oral Oral GastricGastric IntestinalIntestinal RectalRectal


Factors influencing absorption:Factors influencing absorption:

blood flow to the absorption siteblood flow to the absorption site total surface area available for absorptiontotal surface area available for absorption contact time at the absorption surfacecontact time at the absorption surface physic-chemical properties of the drugphysic-chemical properties of the drug first-pass eliminationfirst-pass elimination


First-pass eliminationFirst-pass elimination （（首过消除首过消除）） When a drug is absorbed across thWhen a drug is absorbed across th

e GI tract, it enters the portal circue GI tract, it enters the portal circulation before entering the systemic lation before entering the systemic circulation. If the drug is rapidly mcirculation. If the drug is rapidly metabolized by the liver or intestinal etabolized by the liver or intestinal mucosa, the amount of unchanged mucosa, the amount of unchanged drug that gains access to the systedrug that gains access to the systemic circulation is decreased.mic circulation is decreased.


(2) Parenteral injection(2) Parenteral injection

intramuscular injection ( i.m. ) intramuscular injection ( i.m. ) subcutaneous injection ( s.c. )subcutaneous injection ( s.c. )

DeterminantsDeterminants Local blood flowLocal blood flow Solubility of the drug Solubility of the drug



(3) Others(3) Others

InhalationInhalationTransdermalTransdermal Intranasal Intranasal

TopicalTopical

3.2 Distribution3.2 Distribution

Drug distribution is the process by which a drug Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells interstitium (extracellular fluid) and/or the cells of the tissues.of the tissues.

Blood flow-dependent phase of distributionBlood flow-dependent phase of distribution Selective distributionSelective distribution Tissue-plasma balance: Tissue-plasma balance: importance of measuring pimportance of measuring p

lasma concentrationlasma concentration


Body fluid Body fluid volume:volume:

Sites of drug Sites of drug

distributiondistribution

(1) Binding of drug to plasma proteins(1) Binding of drug to plasma proteins

Bound drug: Bound drug:

can not distribute / inactive temporallycan not distribute / inactive temporally reversible (storage form)/ percentage of bindingreversible (storage form)/ percentage of binding plasma protein capacityplasma protein capacity competitive displacementcompetitive displacement


Competitive displacementCompetitive displacement Class I drugs:Class I drugs: Dose less than available binding sites. Dose less than available binding sites.

Most drug molecules are bound to the proteins and free Most drug molecules are bound to the proteins and free

drug concentration is lowdrug concentration is low..

Class II drugs:Class II drugs: Dose greater than available binding Dose greater than available binding sites. sites. Most proteins contain a bound drug and free drug Most proteins contain a bound drug and free drug

concentration is significantconcentration is significant..Class I + Class II drugs:Class I + Class II drugs: Displacement of Class I Displacement of Class I

drug occurs when a Class II drug is administered drug occurs when a Class II drug is administered simultaneously.simultaneously.


competitive displacementcompetitive displacement

Example:Example:

Class I:Class I: Tolbutamide Tolbutamide (( 甲苯磺丁脲甲苯磺丁脲 ))

Class II:Class II: Sulfonamide Sulfonamide (( 磺胺类药物磺胺类药物 ))

(2) Physic-chemical properties of the drug(2) Physic-chemical properties of the drug

(3) Blood flow and re-distribution(3) Blood flow and re-distribution

(4) Affinity to organs or tissues(4) Affinity to organs or tissues

(5) Barriers(5) Barriers

Blood-brain barrier (BBB)Blood-brain barrier (BBB)

Placental barrierPlacental barrier

Blood-eye barrier Blood-eye barrier


Blood-brain barrier (BBB)Blood-brain barrier (BBB)

Able to pass throughAble to pass through Unable to pass throughUnable to pass through

Small moleculesSmall molecules Large moleculesLarge molecules

Lipid-solubleLipid-soluble Water-solubleWater-soluble

Transporter-mediation Transporter-mediation

Amount of drug passing through blood-Amount of drug passing through blood-brain barrierbrain barrier

Percentage of drug in Percentage of drug in c.s.f.c.s.f.

Increases whenIncreases when

InflammationInflammation

Larger doses usedLarger doses used


BBB permeability BBB permeability increases in increases in

inflammationinflammation

Placental barrier:Placental barrier:

More permeableMore permeable

Drugs for pregnant Drugs for pregnant women:women:

A, BA, B – relatively safe – relatively safe

CC - caution - caution

D,D, XX - toxic - toxic

3.3 Metabolism (biotransformation)3.3 Metabolism (biotransformation) Drug metabolism is the process transforming lipophilic drug iDrug metabolism is the process transforming lipophilic drug i

nto more hydrophilic metabolites, which is essential for the elinto more hydrophilic metabolites, which is essential for the elimination of these compounds from the body and termination omination of these compounds from the body and termination o

f their biological activityf their biological activity..

(1) Metabolism sites(1) Metabolism sites

Liver:Liver: for most of the drugsfor most of the drugs Other organs/tissues:Other organs/tissues: intestine, kidney, lung, plasintestine, kidney, lung, plas

ma, ma, etcetc..


(2) Phases of metabolism(2) Phases of metabolism

Phase I: Phase I: Oxidation, reduction, hydrolysisOxidation, reduction, hydrolysis most drugs are inactivated most drugs are inactivated few (few (prodrugsprodrugs) is activated) is activated

Phase II: Phase II: ConjugationConjugation inactivatedinactivated

Metabolites: Metabolites: more water-solublemore water-soluble easier to excreteeasier to excrete



(3) Enzymes in drug metabolism(3) Enzymes in drug metabolism

Enzymes in Phase I: Enzymes in Phase I: cytochrome-P450cytochrome-P450 many other enzymesmany other enzymes

Enzymes in Phase II: Enzymes in Phase II: acetylase acetylase glucuronosyltransferaseglucuronosyltransferase etc.etc.


Superfamily of cytochrome-P450Superfamily of cytochrome-P450 CYP2A6CYP2A6 （（ cytochrome-P450 / family / subfamily / membercytochrome-P450 / family / subfamily / member ））

(4) Properties of drug metabolism (4) Properties of drug metabolism enzymesenzymes

a.a. Lower selectivity to substrates Lower selectivity to substrates

b.b. Larger individual variability Larger individual variability

c.c. Induction and inhibition by environmental Induction and inhibition by environmental determinants (determinants (including drugsincluding drugs))


Individual variability of isoniazid metabolismIndividual variability of isoniazid metabolism

Rapid acetylationRapid acetylation

Slow acetylationSlow acetylation

Induction of hepatic enzymes by drugsInduction of hepatic enzymes by drugs example: example: phenytoinphenytoin －－ steroids, nifedipinesteroids, nifedipine

Inhibition of hepatic enzymes by drugsInhibition of hepatic enzymes by drugs example: example: verapamilverapamil －－ diazepamdiazepam


肝药酶诱导剂对双香豆素血浓度及凝血作用的影响肝药酶诱导剂对双香豆素血浓度及凝血作用的影响

3.4 Excretion3.4 Excretion

Removal of a drug from the body via a Removal of a drug from the body via a number of routes.number of routes.

Elimination of drugs from the bodyElimination of drugs from the bodyAction on excretory organsAction on excretory organs


3.4 Excretion3.4 Excretion

(1) Excretion routes(1) Excretion routes KidneyKidney BileBile LungLung GI tractGI tract MilkMilk Secretion glandsSecretion glands


(2) Renal excretion(2) Renal excretion

Glomerular filtrattionGlomerular filtrattion renal blood flowrenal blood flow

Active tubule secretionActive tubule secretion specific carriers / competitionspecific carriers / competition

Passive tubule reabsorptionPassive tubule reabsorption urine pH, urine flowurine pH, urine flow


(3) Bile excretion(3) Bile excretion

Carrier-mediated activeCarrier-mediated active

transporttransport

Hepato-enteral circulationHepato-enteral circulation


3.5 Elimination and Accumulation3.5 Elimination and Accumulation

EliminationElimination （（消除消除）） :: MetabolismMetabolism ExcretionExcretion Distribution (stored in fat, hair, Distribution (stored in fat, hair, etcetc))

AccumulationAccumulation （（蓄积蓄积）） :: Dosing rate > elimination rate Dosing rate > elimination rate


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Chapter 1 Pharmacokinetics 药物代谢动力学 §PK process in the body §Kinetic processes