Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl-...

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Absorp’on is quan’ta’ve too Permea’on rate, R P = P Area ΔC Amount absorbed = R P • Time P is membrane par’’on coefficient (related to LogP) Area is effec’ve surface area of membrane ΔC is concentra’on difference for the neutral form of the drug A stomach /A ileum differ 1000 ’mes. That means that even if the frac’on of neutral species in stomach is 100 ’mes greater, s’ll 10 ’mes more compound will be absorbed in the gut. The effect of ’me comes on top. C out C in A=120m 2 A=0.1m 2

Transcript of Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl-...

Page 1: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Absorp'onisquan'ta'vetoo

•  Permea'onrate,RP=PAreaΔC•  Amountabsorbed=RP•Time

–  Pismembranepar''oncoefficient(relatedtoLogP)

–  Areaiseffec'vesurfaceareaofmembrane

–  ΔCisconcentra'ondifferencefortheneutralformofthedrug

•  Astomach/Aileumdiffer1000'mes.Thatmeansthatevenifthefrac'onofneutralspeciesinstomachis100'mesgreater,s'll10'mesmorecompoundwillbeabsorbedinthegut.Theeffectof'mecomesontop.

Cout

Cin

A=120m2

A=0.1m2

Page 2: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

DrugSalts:Bases

Note:HydrochlorideinDrug.HClmaybemisleading,itshouldbejustchloride(Drug+.[Cl-]),samewithH2SO4

Acid[AH]

BasicDrug[B] + -

Drug,BH+Anion

AnionicSaltoftheDrug

plus

Acid Anion Examples

Hydrochloride(HCl) Cl- PyridoxineHCl,PramipexoleHClChlorpromazineHCl,Demeclocycline..DemethylchlortetracyclineNalbuphine,ChlorhexidinePropafenone,MitoxantroneLincomycin,Ro'go'neVilazodone,Naphazoline

SulfuricAcid SO42- Dextroamphetamine,Hydroxychloroquine

Ace'cAcid(acetate) CH3COO- Leuprolide,Goserelin,Desmopressin,…

cocainehydrochloride

+

Page 3: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

DrugSalts:AcidsBaseB,e.g.NaOH

AcidicDrugAH

e.g.R-COOH - +Drug

ion,[A-] Ca'on

Ca'onicSaltoftheDrug

plus

OH-Base Ca;on Examples

Sodium Na+ Ecabet,Diclofenac,Indomethacin,Benzoate,Salicylate

Calcium Ca++ Atorvasta'n,CalciumGluceptate

Potassium K+ PenicillinVPotassium,Losartan

Ca++needstwonega'vecharges

CalciumGluceptate

Warning:donotforgettousecorrectmolecularweightofthesalt

Page 4: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Salts:summary•  Stoichiometry:makesure

thatthetotalformalchargeiszero(e.g.[D-]2Me2+)

•  Ambiguityofchemicalrepresenta'on:[DH+][Cl-]vs[D][HCL],MolWeight.

•  Solubilityofcrystals:usuallybecerthannon-salt,butdiffersbetweendifferentsalts.

•  Iden8calinSolu8on:Oncethesaltisdissolveditbecomesiden'caltothenon-saltformofthedruginsolu'on

•  Resonance:Example,sulfate:perfecttetrahedronwithtotalnega'vechargeof-2distributedbetween4nega'veoxygensandoneposi'vessulfur.

Page 5: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Saltswithbecersolubility:example•  Example:

–  Phenobarbital,awhitepowder,isaweakacidwithlimitedsolubilityinwater,

–  thesodiumsaltofPhenobarbital,alsoawhitepowder,thesaltoftheweakacid,nowwatersoluble

•  pKa=7.41

•  pH(satur.sol)5~10.•  Solubility:1g/L1g/10mL

Epoprostenol.Na+ProstacyclinI.V.vasodilatorinischemia&PH

Na+

Moreexamples:Naproxen NaproxenSodiumFenoprofen FenoprofenCalciumPenicillinG PenicillinGPotassium

Page 6: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Moreanionsforbasicdrugs•  Base Salt/ConjugateAcid•  Diphenhydramine DiphenhydramineHCL•  Glucosamine Glucosaminesulfate•  Epinephrine Epinephrinesulfate•  Ephedrine EphedrineHCl•  Atropine Atropinesulfate•  Tetracycline TetracyclineHCl

•  Mostofthesedrugs,asyoucantellbytheirname,are"amines",whichmeanstheyareweakbases

•  AcetateCH3COO−(ace'cacid)•  CarbonateCO3

2−,carbonicacid)•  ChlorideCl−(hydrochloricacid)•  CitrateHOC(COO−)(CH2COO−)2(citricacid)•  CyanideC≡N−(hydrocyanicacid)(toxic)•  NitrateNO3

−(nitricacid)•  NitriteNO2

−(nitrousacid)•  PhosphatePO4

3−(phosphoricacid)•  SulfateSO4

2−(sulfuricacid)Sodium-nitroprusside,-vasodilator

Page 7: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

SolubilityandPermeability

Twooppositerequirements:•  Solubilityisgoodforchargedcompoundswithmul'plepolargroups(e.g.pep'des)

•  Permeabilityisgoodforhydrophobicandapolarcompounds

Twosolu'ons:•  Beexactlyinthemiddlewiththesamechemicalstructure(minority)

•  Beabletochangeviaenzyma'cac'va'on(prodrug)oradoptalterna'vechargedforms

Page 8: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Solubility,LogP,andLogD

•  Notallunchargedcompoundsareinsoluble

•  Notallpolarorchargedcompoundscannotpermeateamembrane

•  Itisaquan8ta8vemacer•  Threemeasurablequan''esareusedtocharacterizeadrugsubstance:LogSw,LogPandLogD

water

membrane

Page 9: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

DrugSolubility:defini'on•  Water(aqueous)solubility(SW)isthemaximumamountofasubstancethatcandissolveinwater.SWdependsonP,T.

•  Swisinmoles/L(M).Watchformg/Lormg/dL!

•  LogSw(orLogS)=Log(Sw)

Sucrose

Succinylcholine>10M!Butnotfatsoluble Mitotane:0.1mg/L

Page 10: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

SolubilityandGibbsenergy

•  Solubilityisdefinedbyadifferencebetweenthefreeenergyinthecrystalform(primarilyenthalpy)andthedissolvedform(solva'on,differententropyterms)

•  Theentropy-of-mixingcontribu'ontodissolu'on(andrigidbodyrota'on/transla'on)doesnotdependonchemicaltypeandinterac'ons.Themaindifference:–  thenumberoffreedrotatablebonds,hydrophobicsurface,(ΔS);

–  intermolecularinterac'onsinthecrystalvswater,ΔH

water

µ 0aq + RT lnSW = µ 0s

Page 11: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

DrugandProteinCrystals•  HighlyorderedarraysofmoleculesheldtogetherbyNONCOVALENTinterac'ons

•  Crystallaoceisa3Drepeatofthesameunit.Itisdefinedbythesidesandtheanglesofaparallelepipeda,b,c,α,β,γ

Page 12: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Polymorphism•  Compoundscancrystallizeasdifferentpolymorphs(differentmolecularconforma'onandpacking,cell)

•  Polymorphscanhavedrama'callydifferentsolubility,mel'ngpoint,'meofdissolu'on,habits

A

AA

AA

AAA

A

AA

A

A

A

AA

AA

AAA

A

AA

A

A

A

A

A

A

A

AA

A A

AA A

A AA

AAA A

AA A AA

A

A

A

A

A

AA

A A

AA A

A AA

AAA A

AA A AA

G

AA

AAA

AAA

G

G

G

GGG

A

A

A

GG

AG

G

AA

AAA

AAA

G

G

G

GGG

A

A

A

GG

AG

C-A+

C- C-C-

C- C-C-C-

A+

A+

A+A+

A+

A+A+

A+C-

A+C- C-C-

C- C-C-C-

A+

A+

A+A+

A+

A+A+

A+

Salts

Co-crystals??

PolymorphsSameAPISameAc;veMoiety

DifferentAPI

WhereDoCo-CrystalsFit?

IsaNewRegulatoryClassofSolidsNeeded?

Adoptedfromthepresenta'onofFDA-Div-DirectorDr.AndreS.Raw

API:Ac'vePharmaceu'calIngridients

Page 13: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Crystalhabitsofdrugs•  Thesamesymmetrygroupmayleadto

differentsizeandshapeofacrystal•  Crystalhabits(andsize)mayinfluence

–  injec'on(plates:easy,needles:difficult),–  tableong(easyforcompression)–  rateofdissolu'on

•  Habits:–  Acicular(needle-like)–  Prisma'c,pyramidal,tabular, equant,

columnaranlamellartypes•  Habitdeterminants:

–  Solvent–  Temperature–  Concentra'onofimpuri'es

Page 14: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Snowflakes&drugcrystals

•  Snowflakesareaverywellknownexample,wheresubtledifferencesincrystalgrowthcondi'onsresultindifferentgeometries.

Page 15: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Par'clesizeandtherateofdissolu'on

•  Considerthesurfaceofthefixedamountofcompoundasthefunc'onoflinearmicro-crystalsize,d,andthetotalvolumeV

•  Fornon-cubicshapes,calculatetheAreaasafunc'onoftotalvolumeandshape.

dVd

dVA 66 23 ==

d

Forsimplecubicshapethetotalareaofmicrocrystalsurfaceisinverselypropor'onaltothecrystalsize

Page 16: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

LogDandMembranepermea'on

•  Togetinsidethecelladrugneedtogetinsidethemembranefirst

•  Par88oningbetweenwaterandamembraneischaracterizedbyLogPforharddrugsandLogDforionizabledrugs

•  Nega'veLogD:toopolar•  Largeposi'veLogD:–toohydrophobic

Page 17: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Thequan'ta'veoctanol/watermodel.MoleculeDoesnotChange:LogP

wat

oct

CCP loglog =

OH

O

OH

Owater octanol

•  PmeansPar''on•  Octanol~membrane•  Freeenergydifference

HOH

RTCCP

CRTCRT

ow

w

o

ooww

3.2loglog

lnln00

00

µµ

µµ

−==

+=+

oo

ww

CC,

,0

0

µ

µ druginwaterdruginoctanol

BenzoicAcid:LogP=1.87

Page 18: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Theoctanol/watermodel:LogD

wat

oct

AHAHP][][loglog =

OH

O

OH

Owater octanol

watwat

octoct

AAHAAHD][][][][loglog

+

+=

O

O

O

O

LogDistheapparentpar''oncoefficient

Page 19: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

LogDdependsonLogPoftheneutralformandpH-pKa

logP ≡ log [AH ]oct[AH ]watOH

O

OH

O

logD = logP – log(1 + 10pH-pKa) for acids ≈ logP – (pH – pKa) (for pH> pKa+1, charged form dominates)

water octanol

watwat

octoct

AAHAAHD][][][][loglog

+

+=

O

O

O

O

logD = logP – log(1 + 10-(pH-pKa)) for bases ≈ logP – (pKa–pH) (for pH < pKa-1, charged form dominates)

LogDisapparentLogP

pKa=4.2;LogD(pH=7.2)≈1.87-3=-1.13

AtpHvalueswhereneutralformsdominatesinwater:LogD ≈ LogP

AtpHvalueswherechargedformsdominatesinwater:LogD is smaller than LogP:

Page 20: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Ourbodyiswatchingthelipophilicityofxenobio'cs

KidneystakecareofthepolarLivertakescareofthehydrophobs

•  Polarandchargedmolecules–renalclearance(fast).*Probenecid(OATinh.)increasesexcre'onofuricacidbutblocksrenalexcre'onofandotherdrugs.

•  BBBblocksthepolarandchargedcompounds

•  Hydrophobiccompoundsaremadeintopolaronesbymetabolism.Cyp450smodifyhydrophobiccompounds,

Page 21: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Lipophilicity–adeterminantofpharmacokine'cs

•  LogD,pH=7.4(fromShalaeva,““NewTechnologiestoIncreaseDrugCandidateSurvivability”,Philadelphia,2002)

•  <0 Toopolar.Intes'nalandCNSpermeabilityproblems.Suscep'bletorenalclearance

•  0to1 Agoodbalancebetweenpermeabilityandsolubility.Atlowvalues,(morepolar),CNSpermeabilitymaysuffer

•  1to3 Op;mumrangeforCNSandnon-CNSorallybioavailabledrugs.Lowmetabolicliabili;es,generallygoodCNSpenetra;on

•  3to5 Solubilitytendstobecomelower.Metabolicliabili'es.

•  Above5Lowsolubilityandpoororalbioavailability.Erra'cabsorp'on.Highmetabolicliability,althoughpotencymays'llbehigh.

0

1

2

3

4

5

LogD

Page 22: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

CytochromeP450•  R-H+O2+2e=>R-OH+H2O(usesNADPH)•  AddingOneOxygen:monooxygenase•  R-OHisfurthermodifiedbysolubilizingsulfateorsugars•  bergamoon,dihydroxybergamoon,andparadicin-Ain

grapefruitjuice(andotherjuices)havebeenfoundtoinhibitCYP3A4,-overdose

•  Saint-John'swortinducesCYP3A4,butalsoinhibitsCYP1A1,CYP1B1,andCYP2D6,-noac'on

•  TobaccosmokinginducesCYP1A2,..

4-hydroxy-tamoxifenintheestrogenreceptorpocket

CytochromeP4502B4withparoxe'ne

Page 23: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Problema'cpermeability

•  Naturalproducts(bigandpolar)– permeabilityamajorproblem

•  Pep'domime'cs(longandpolar)– permeabilityamajorproblem

•  RNAi•  CNStargets('ghtbarrier)– Blood-brainpermeabilityamajorproblem

Page 24: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Predic'ngLogP/LogD•  LogPisrelatedtothePOLARSURFACEAREA(PSA):thetotalsolventaccessibleareaofpolaratoms

•  Moresophis'catedmethodstopredictLogPandLogD(cLogP,MolLogP,etc.)

Compound LogP

Methane(CH4) 1.1

Propane(C3H8) 2.24

Pentane(C5H12) 3.26

Hexane(C6H10) 3.76

�1-Pentanol�(C5H12O) 1.35

1-Hexanol(C6H13OH) 1.86

Page 25: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Solubility/Permeabilitygate•  Permeability– PSA>140-200Å2isproblema'cforsystemicdistr.– PSA>75Å2isproblema'cforCNSdelivery

•  Solubility– Solubility<5-20µg/mLisproblema'c

•  Poorpermeabilityisworsethanpoorsolubility-noeasyformula8onfixexists

•  Intra-molecularH-bondsimprovepermeabilitywithminimalaffectonsolubility.

Page 26: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Prodrugstoimprovesolubility

NH

Cl

OO

O-Na+O

O

ClOH

O2N

NH

Cl

OH

O

ClOH

O2N

O-Na+O

O

OH

Esterase

or Water

Chloramphenicol Succinate

Chloramphenicol

Sodium succinate

Page 27: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Howtofixpermeability•  Pro-drug–addahydrophobicgroupthancanbecleavedoffinsideacell– difficultextrapola'onfromanimaltoman

•  Changethestructure– e.g.introduceintramolecularH-bond

Prodrug

Drug OPromoiety

OOH Promoiety

Promoiety ODrug

O

Drug OH

O

Promoiety OH

OOH Drug

or

+

+

Page 28: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Ethylestersandalkalinehydrolysis

•  Ethylestersarefrequentlyusedasapro-moiety

•  Theycanalso(atsomelevel)behydrolizednon-enzima'cally

Alipophilictail

Page 29: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Prodrugtofixpermeability

•  Enapril(ACEinhibitor,hypertension)ishydrolyzedtoEnaprilatbyesterase.Byproduct:ethanol

•  Aspartame/NutraSweetByproduct:methanol

Bewareofmethylesters

Enapril+H2OtoEnaprilat+ethanol

+H2O

Page 30: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Prodrug:howtotricktheBrain

•  Pretendtobeanaminoacid•  Valaciclovirtoaciclovir(herpesan'viral)byesterase:transport

•  LevodopatoDopaminebydecarboxylase–  BrainhasaspecifictransportsystemforL-aminoacids

Dopamine

Page 31: Absorp’on is quan’tave too - ruben.ucsd.eduruben.ucsd.edu/17/u15.pdf · Hydrochloride (HCl) Cl- Pyridoxine HCl, Pramipexole HCl Chlorpromazine HCl, Demeclocycline .. Demethylchlortetracycline

Prodrug:IncreasedBBpermeability

NH2 OH

O

GABA (gamma-amino butyric acid)

Drug:

N

Cl

F NH2

OOH

Progabid

Prodrug:

• an'-convulsiveneurotransmicer• orallyinac've• nopenetra'onofblood-brainbarrier

• orallyac've• rapidpenetra'onofblood-brainbarrier