admet pofarm

8/9/2019 admet pofarm

1/61

02-12-201

The pharmacokinetic phase (ADME)

Absorption is the passage of the drug from its site ofadministration into the general circulatory system after enteraladministration

Distribution is the transport of the drug from its initialpoint of administration or absorption to its site of action.

Metabolism is the biotransformation of thedrug into other compounds (metabolites) thatare usually more water soluble than theirparent drug and are usually excreted in the

urine.

Excretion is the process by whichunwanted substances are removedfrom the body 1

Some of the multidisciplinary interfaces with PK

Pharmacokinetics

toxicology

clinical

Marketing

Pharmaceutics

Regulatory

MedicinalChemistry

Clinicalpharmacolo

gy

biology

2
http://www.google.pt/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=1rslJWk2vAInqM&tbnid=XbhpM1BRwMOlGM:&ved=&url=http://www.picstopin.com/2560/-size-112k-2560x1600-from-%E5%8D%A1%E9%80%9A-%E7%AE%80%E6%B4%81-%E6%A1%8C%E9%9D%A2-11304-72k/http:||photo*aoaob*com|imgsrc*baidu*com|forum|pic|item|ffea080896fdea6ae8248882*jpg/&ei=Ho5vUurIG4Wx0QXF5oCwCQ&psig=AFQjCNEpkytrX0hinoZf-y22vZ1BaeCtxw&ust=1383128777312348


2/61

02-12-201

ADMET em Qumica Medicinal

3

4

solvel

estvel

selectivo

activo

seguro

PK

novo Bonsfrmacos

Bonslderes

ADMET em Qumica Medicinal

Drug-like properties confer good ADME/Tox characteristics to a compound.

Medicinal chemists control properties through structure modification.

Biologists use properties to optimize bioassays and interpret biological experiments


3/61

02-12-201

5

Causas de abandono no desenvolvimento de frmacos

Edward Harvel Kerns, Li Di, Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization, Academic Press, 2008.

Relationship of structural properties and ADME events

6


4/61

02-12-201

7

Parallel structure activity relationships (SAR) and

structure property relationships (SPR) strategies SAR SPRIn vitro assays In vitro assayHTS IntegrityEnzyme/receptor assays SolubilityCell-based assays Permeability

LipophilicitypK aStabilityMetabolite screeningTransportersCYP450 inhibitionCell exposurePlasma protein binding

In vivo assays In vivo assaysAnimal model PK/exposure

8

A typical parallel progression strategy for lead optimization

In vivo


5/61

02-12-201

9

Integrity LC-MS Start SAR with known purity and correct

structure

Aggregation DLS, EM Avoid following the non-specific hits

Solubility Direct UV Interpret in vitro/in vivo assay

results

Turbiditimetry Enhance oral bioavailability

Develop formulation strategy and potential

salt forms

Permeability PAMPA Interpret cell-based assay results

Caco-2 Enhance oral absorption

MDCK Diagnose transport mechanism

PAMPA-BBB Predict BBB penetration

Develop pro-drug strategy

Impact of pharmaceutical profiling assays in drug discovery

Assays Methods Impact in drug discovery

*DLS, dynamic light scattering; EM, electron microscopy.

10

Pgp efflux Monolayer efflux Diagnose efflux transport mechanismCalcein-AM Improve oral absorption, BBB penetrationATPase Reduce cancer cell Pgp-mediated resistance

Lipophilicity Shake flask Develop QSAR and QSPRHPLC Predict ADME/TOX propertiesMEEKC

pKa SGA Predict effect of pH on solubility andpermeability

CE Facilitate process for salt selectionStability Robot and LC-MS Diagnose poor pharmacokinetics

Enhance metabolic stabilityInitiate metabolite/degradant identification

CYP450 inhibition Fluorescence Minimize toxicity due to drug drugInteractions

LC-MS-MSRadiometric

Impact of pharmaceutical profiling assays in drug discovery

Assays Methods Impact in drug discovery


6/61

02-12-201

11

Drug discovery stages

Barriers to Drug Exposure in Living Systems

membranes, pH, metabolic enzymes, andtransporters

12


7/61

02-12-201

Gastrointestinal Tract Barriers

(A) passive diffusion

(B) endocytosis

(C) uptake transport

(D) paracellular

transport

(E) efflux transport

Permeation mechanisms

pH Values and Transit Times of Gastrointestinal Tract Regions

GI tract region Average pH, fasted Average pH, fed Transit time (h)Stomach 1.4 2.1 3 7 0.5 1Duodenum 4.4 6.6 5.2 6.2Jejunum 4.4 6.6 5.2 6.2 2 4Ileum 6.8 8 6.8 8

13

Blood stream sink enhances permeation pH 7.4 creates a trap for bases blood flow increases concentration gradient Capillary to

Portal Vein

GI EpithelialCell Layer

Uptake transport against gradient Salt form

enhancesdissolution

pH increases

ionization of basesfor solubility

GI Lumen

Reducedparticle size enhancessurface areafor dissolution

Formulation dispersion tosmaller particlesor solution enhancessolubility

Food Effect stimulates bile release

Bile salts solubilize

Drug SolidParticle

14

Absorption Enhancement in the Intestine


8/61

02-12-201

Barriers in the Bloodstream

Plasma Enzyme Hydrolysis

Plasma Protein Binding

Red Blood Cell Binding

Barriers in the Liver

Metabolism

Biliary Excretion

Barriers in the Kidney

Blood Tissue Barriers

Tissue Distribution

15

16


9/61

02-12-201

17

BARREIRA HEMATOENCEFLICA

Protege o crebro e a medula

Permite a entrada de oxignio e nutrientes

POUCOS FRMACOS CONSEGUEM ATRAVESSAR A BHE

Caractersticas fisico-qumicas adequadas

Processo de transporte adequado

PharmacokineticsTypical variations in the concentration of a drug with time

Schematic representation of a therapeutic window

18
http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8


10/61

02-12-201

Pharmacokinetic Parameters: Definitions, Calculations, andApplications In Discovery

19


20


11/61

02-12-201


21

General PK Parameter Goals for Discovery Compounds Pharmacokinetic Symbol High LowParameter

Volume of distribution Vd >10 L/kg 45 mL/min/kg 70 mL/min/kg 15 mL/min/kg 3 h 3 h 8 h 50% 2,000 hng /Ml 3 h


12/61

02-12-201

Pharmacokinetic Parameters of Selected Drug Compounds

23


24


13/61

02-12-201


25

26

Molculas que contm grupos

funcionais e/ou possuem

propriedades fsicas consistentes

com frmacos existentes

Advanced Drug Delivery Reviews 54 (2002) 255 271

Conceito Drug-like

Compostos que possuem propriedades

ADMET suficientemente aceitveis para

completar ensaios clnicos de fase I Christopher A. Lipinski


14/61

02-12-201

27

Um composto para exibir absoro/permeabilidade dever ter:

- Um peso molecular < 500

- No mais que 5 grupos doadores de interao de H

(somando OHs e NHs)

-No mais que 10 grupos aceitadores de interao de H

(somando Os e Ns)

- Um valor de logP calculado


15/61

02-12-201

Lead-likeness

MW 460 4 Log P 4.2

Log of water solubility (Log S W)5

Rotatable bonds 10

Rings 4

Hydrogen-bond donors 5

Hydrogen-bond acceptors 9

Bioavailability (%F) 30% Clearance (Cl) < 30 mL/min/kg in rat

0 LogD7.4 3

Binding to cytochrome P450 isozymes = low

Plasma protein binding 99.5%

Acute toxicity and chronic toxicity = none (in

therapeutic window)

Genotoxicity, teratogenicity, carcinogenicity =

none (at dose 5 10 times therapeuticwindow)

29

Drug absorption pathway

30


16/61

02-12-201

31

The multiple mechanisms of transport through the intestinal epithelium

Solubility

Ksp = [C+]x[A-]solubility product

Henrys Law: Cg = KgPg

solution

32


17/61

02-12-201

Comparison Kinetic Solubility Thermodynamic Solubility

Initial State DMSO Stock Solid Crystals

Mixing Time Variable Long mixing

Temperature Room Temperature Controlled Temperature

Equilibrium Not Established Established

Crystal Form Meta-Stable Forms Stable Form

Target Solubility 100 g/mL 10 mg/mL

Throughput 150 Compounds/day 20 Compounds/day

Material 1.5 mg for 4 pHs 100 mg for 20 solvents

Comparison of Kinetic and Equilibrium Solubility

33

Applications of Solubility in Lead Optimization

Solvents Commonly Used for Solubility Determination of DevelopmentCandidates in Late-Stage Drug Discovery

Physiological Buffers Formulary Solvents LipophilicitypH 1 Tween 80 OctanolpH 4.5 PEG 200 LabrasolpH 6.6 PEG 400 CyclohexanepH 7.4 Phosal 53 MCTpH 9 Phosal PGSGF Benzyl AlcoholSIF EtOHSIBLM Corn OilPlasma 2% Tween / 0.5% MC

34


18/61

02-12-201

Correlation between Solubility, Permeability and Dose

35

Delivering Drug to the Test System

Typical compound solubilization curve in a cosolvent systemsuch as DMSO /water (solid line).

Solubility, Solubilization and Dissolution in Drug Delivery During LeadOptimization

36


19/61


20/61

02-12-201

2

Salt formation

Examples of the acids and bases used to form the salts of drugs

the water-insolubleembonate salt isalmosttasteless

very bitter taste

39

Examples of the structures of acids and baseswhose structures contain water solubilising groups

40


21/61

02-12-201

2

Poor absorption and bioavailability after oral dosing Insufficient solubility for IV dosing Artificially low activity values from bioassays Erratic assay results (biological and property methods) Development challenges (expensive formulations and increased

development time) Burden shifted to patient (frequent high-dose administrations)

Solubility

BiopharmaceuticsClassification

System

41

High Solubility Low Solubility

High Permeability Class I Class IIDissolution rate limits Solubility limitsabsorption absorption

Diltiazem FlurbiprofenLabetalol NaproxenEnalaprilPropranolol

Low Permeability Class III Class IVPermeability limits Significant problems for oralabsorption drug delivery are expected

Acyclovir TerfenadineFamotidine FurosemideNadolol

42


22/61

02-12-201

2

The effect of pH on the solubility of acidic and basic drugs

Henderson Hasselbalch equation

The pKa of aspirin, a weak acid, is 3.5. Calculate the degree of ionisation of aspirin in the (a)stomach and (b) intestine if the pH of the contents of the stomach is 1 and the pH of thecontents of the intestine is 6.

43

Partition

44


23/61

02-12-201

2

Structure Modification Strategies to Improve Solubility

Add ionizable groupReduce Log PAdd hydrogen bonding

Add polar groupReduce molecular weightOut-of-plane substitution to reduce crystal packingConstruct a prodrug

Log S = 0.8LogPow 0.01(MP25)

S = [HA]+ [A] AcidS = [B] + [HB+] Base

45

The incorporation of water solubilising groups in a structure

the type of group introduced; whether the introduction is reversible

or irreversible; the position of incorporation; the chemical route of introduction

46


24/61

02-12-201

2

Introduction of a side chain with a carboxylic acid or amineenhances the solubility of artemisinin.

47

Carboxylic acid groups by alkylation

Carboxylic acid groups by acylation

48


25/61

02-12-201

2

Phosphate groups Sulphonic acid groups

Polyhydroxy and ether residues

49

Incorporation of basic groups

50


26/61


27/61

02-12-201

2

Add Polar Group Reduce Molecular Weight

53

Reduction of Crystal Packing Energy

Introduction of Ethyl Group Disrupted -Stacking, ReducedCrystal Packing Energy and Improved Solubility

54


28/61

02-12-201

2

Out-of-Plane Substitution

Construct a Prodrug

Strategies for Improving Dissolution Rate55

Particle Size Reduction

High Energy Solids

Solubility Enhancement

Cosolvents

Ionization and pH Adjustment

Surfactants

Dispersed Lipid Phases

Complexation

Supersaturation

Enabling Formulation Strategies for Drug Delivery

56


29/61

02-12-201

2

Permeability Permeability is the velocity of molecule passage through a membrane barrier.

Permeability is a determinant of intestinal absorption and oral bioavailability.

Optimizing passive diffusion is productive because it is the predominant

mechanism for absorption of most commercial drugs.

Permeability is increased by removing ionizable groups, increasing Log P , and

decreasing size and polarity.

57

58


30/61

02-12-201

3

59

The Caco-2 permeability assay

human epithelial colorectaladenocarcinoma cells

Comparison of PAMPA and Caco-2 Assay

Comparison PAMPA Caco-2

Membrane Phospholipid Cell Monolayer

Mechanisms Passive Passive, Influx,

Efflux, Metabolism

Throughput 500 / week 30 / week

Cost < $1 / sample ~ $30 / sample

Manpower 0.35 FTE 2 FTE

60

PAMPA=parallel artificial membrane permeability assay


31/61

02-12-201

3

61

Passive Diffusion Permeability

Passive diffusion across a membrane is affected by thesolution pH and compound p K a. In this PAMPApermeability experiment, acidic, basic, and neutralcompounds have different permeability at different pHvalues.

Permeability of IonizableCompounds is pH-Dependent

62


32/61

02-12-201

3

Drug Drug Serum Protein complex

Distribution

I. Action of the membrane on drug molecules

Diffusion through membranes may become rate limiting

Membrane may completely prevent diffusion to the active site

Solvation of the drug in the membrane may lead to conformational changes

of the drug molecule

II. Drug action on membrane properties

Drug may change conformation of acyl groups (trans-gauche)

Drug may increase membrane surface

Drug may increase membrane fluidity

Drug may change membrane potential and hydration of head groups

Drug may change membrane fusion

Drug Membrane Interaction


33/61

02-12-201

3

Transporters

Uptake

Oligopeptide transporters (PEPT1, PEPT2)

Organic anion transporters (OATP1, OAT1,

OAT3)

Organic cation transporters (OCT1)

Bile acid transporters (NTCP)

Nucleoside transporters

Vitamin transporters

Glucose transporters (GLUT1)

Efflux

P-glycoprotein (Pgp, MDR1)

Breast cancer resistance protein (BCRP)

Transporters Affecting Gastrointestinal Absorption of Some Drugs

Uptake Transporters

Organic Anion Transporting Polypeptides (OATPs, SLCOs)Di/Tri Peptide Transporters (PEPT1, PEPT2)Organic Anion Transporters (OATs)Organic Cation Transporter (OCT)Large Neutral Amino Acid Transporter (LAT1)Monocarboxylic Acid Transporter (MCT1)Glucose Transporter (GLUT1)Sodium Dependent Taurocholate Co-transporting Polypeptide (NCTP)


34/61

02-12-201

3

Efflux Transporters

P-glycoprotein (MDR1, ABCB1)

BCRP, MRP2

Rules for Pgp Efflux Substrates

N + O 8 MW > 400Acid with pKa > 4

Pgp substrate Pgp non-substrate

N+O 4 MW < 400Base with pKa < 8


35/61

02-12-201

3

Structure Modification Strategies to Reduce Pgp Efflux

1. Introduce steric hindrance to the hydrogen bond donating atoms by:

a. Attach a bulky group

b. Methylate the nitrogen

2. Decrease H-bond acceptor potential

a. Add an adjacent electron withdrawing group

b. Replace or remove the hydrogen bonding group (e.g., amide)

3. Modify other structural features so that they may interfere with Pgp binding,

such as adding a strong acid

4. Modify the overall structures Log P to reduce penetration into the lipid

bilayer where binding to Pgp occurs

Increasing steric hindrance reduces Pgp efflux

Pgp efflux at the BBB was decreased byadding a carboxylic acid moiety


36/61

02-12-201

3

71

BARREIRA HEMATOENCEFLICA

Protege o crebro e a medula

Permite a entrada de oxignio e nutrientes

POUCOS FRMACOS CONSEGUEM ATRAVESSAR A BHE

Caractersticas fisico-qumicas adequadas


72

Pardridge

n inter. H < 8-10

PM < 400-500

No cidos

Pardridge, W. M. (1995).Transport of small molecules through the blood-brainbarrier: Biology and methodology . Advanced DrugDelivery Reviews,15 , 5 36.

Spraklin

n dadores H < 2

n aceitadores H < 6

Propriedades FQ que afectam grandemente permeao trancelular passiva

Clark e Lobell

N + O < 6

PSA 0

PM = Peso molecularPSA = rea superfcie polarLog D = log. Coeficiente de distribuioCLog P = log. coeficiente de partilha calculado
http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8http://images.google.pt/imgres?imgurl=www.ispub.com/xml/journals/ija/vol3n2/braina.jpg&imgrefurl=http://www.ispub.com/journals/IJA/Vol3N2/inhal1.htm&h=161&w=202&prev=/images?q=anesthetics&svnum=10&hl=pt-PT&lr=&ie=UTF-8


37/61

02-12-201

3

73


Aproveitamento do transporte das substncias fisiolgicas

Ex: L-DOPA (di-hidroxifenilalanina) absorvida como a.a. activo

posteriormente transformada em dopamina

Structure Modification Strategies to Improve Brain Penetration Reduce P-glycoprotein efflux

Reduce hydrogen bonds

Increase lipophilicity

Reduce molecular weight

Replace carboxylic acid groups

Add an intramolecular hydrogen bond Modify or select structures for affinity to uptake transporters


38/61


39/61

02-12-201

3

Plasma Stability

Several functional groups are susceptible to plasma degradationand include the following:

EsterAmideCarbamateLactamLactoneSulfonamide

Soft Drugs


40/61


41/61

02-12-201

4

Increased steric hindrance of the lactamcarbonyl increased plasma stability

Introduce electron-withdrawing group todecrease plasma stability and increaseclearance to avoid adverse effects usingantedrug approach

Solution Stability

specific conditions and components of a wide range of solutions cancause compound instability

pHWaterCounter ions of saltsSolution components (e.g., dithiotheital (DTT))ExcipientsEnzymes

High-performance liquid chromatographymodifiers (especially if concentrated afterpurification)TemperatureLightOxygen


42/61

02-12-201

4

Structure Modifications Strategies for Solution Stability Improvement

Eliminate or modify unstable group

Add an electron-withdrawing group


43/61


44/61

02-12-201

4

Plasma Protein Binding

Compounds can bind to albumin, 1-acid glycoprotein, or lipoproteins in blood.

Binding reduces free drug in solution for penetration into tissue to reach thetherapeutic target or to the liver and kidney for elimination.

Species differences in plasma protein binding

Classification of Acidic Drugs for HSA Binding

Types of drugs I II IIIReference drugs Warfarin diazepam Indomethacin PhenytoinBinding proteins HSA HSA HSABinding processes Saturable Saturable and nonsaturable

NonsaturableAssociation constant (M1) 104106 103 105 102103 Binding sites per molecule 1 to 3 6 Many

Classification of Non-ionized and Basic Drugs

Types of drug IV V VIReference drugs Digitoxin Erythromycin ImipraminepKa 8.8 9.5Binding protein HSA (NS) HSA (NS) HSA (NS), 1-AGP (S), HDL(NS),

LDL (NS), VLDL (NS)Drug plasma saturation No Possible Possible


45/61

02-12-201

4

PPB Effects

Retain drug in plasma compartment Restrict distribution of drug into target tissue (reduce volume of distribution [Vd]) Decrease metabolism, clearance, and prolong t Limit brain penetration Require higher loading doses but lower maintenance doses

Impact of PPB on Distribution

Restrictive and Permissive Effects of PPB on Drug Disposition

Drug Free drug in plasma (%) Volume of distribution (L/kg)RestrictiveFurosemide 4 0.2Ibuprofen


46/61

02-12-201

4

High PPB can restrict BBB permeation

Blood BBB Brain

Free drug molecules permeate through the BBB

Effect of PPB on Clearance

Restrictive and Permissive Effects of PPB on Liver Extraction

Drug Bound drug in plasma Liver extraction ConsequencePropranolol >90% >90% PermissiveWarfarin >99%


47/61

02-12-201

4

Structure Modification Strategies for PPB

Structure Modification Strategies to ReducePPB in Order of Highest to Lowest Potential Effect

Structure Modification Strategy

Reduce lipophilicity (Log P for acids, Log D 7.4 for nonacids)

Reduce acidity (increase p K a of the acid)

Increase basicity (increase p K a of the base)

Reduce nonpolar area

Increase PSA (increasing PSA increases hydrogen bonding)

Excretion


48/61

02-12-201

4

95

Drug/metabolite Enantiomer Clearance Units RatioAcebutolol R CLR 124 mL/min 1.03

S 120Diacetolol R CLR 70 mL/min 1.32(active metabolite S 53of acebutolol)Atenolol (+) CLR 109.7 mL/min 1.03

(-) 112.5Chloroquine (+) CLR 276 mL/min 1.03

(-) 267(+) CLRu 824 1.59(-) 519

Disopyramide* (-)-R CLR 0.75 mL/min/kg 1.17(+)-S 0.64(-)-R CLRu 6.26 1.40(+)-S 8.75

Mondesisopropyl (-)-R CL R 1.97 mL/min/kg 2.09disopyramide (+)-S 4.11(following (-)-R CLRu 3.21 2.19administration (+)-S 7.02of the drug)

Renal Clearance of Drug Enantiomers in Man

CLR, CLRu, and CLTS are the total, unbound, and tubular secretion clearances, respectively*drug administered as the individual enantiomers

96

Drug/metabolite Enantiomer Clearance Units Ratio

Metoprolol (-) CL R 69 mLmin 1.09(+) 75

Mexiletine (-) CLR 0.5 mL/min/kg 1.0(+) 0.5

Ofloxacin (+)-R CLR 7.53 L/h 1.05(-)-S 7.14

Pindolol (+)-R CLR 200 mL/min 1.20(-)-S 240(+)-R CLRu 453 1.18(-)-S 534(+)-R CLTS 157 1.25(-)-S 196(+)-R CLR 170 mL/min 1.31(-)-S 222

(+)-R CLTS 121 1.40(-)-S 169

Prenylamine (-)-R CLR 1.3 mL/min 3.08(+)-S 4.0

Terbutaline* (-) CL R 1.5 mL/min/ kg 1 1.80(+) 2.7

Tocainide* (-) CLR 55 mL/min 1 1.0(+) 55

Tranylcypromine (-) CL R 15.3 mL/min 1 1.63(+) 24.9(-)* 8.1 mL/min 1 2.19(+) 17.7


49/61

02-12-201

4

97

a drug that is rapidly metabolized, that is, a drug with low metabolic stability, will requiremultiple daily dosing or continuous infusion to maintain an adequate therapeutic plasmalevel. Likewise, a highly stable drug, that is, a drug that is not readily metabolized andeliminated, could have a prolonged halflife, which might influence its safety.

Drug metabolism is a key determinant of several important drugproperties

Metabolic stability

Drug drug interactions

Drug toxicity

a major cause of drug drug interactions is the interference of the metabolism ofone drug by a co-administered drug.

a drug might be rendered non-toxic (i.e. detoxification) or more toxic (i.e.metabolic activation) by metabolism.

Figure 1. Hypothetical plot of a plasma drug concentration vs. time curve in theabsence and presence of an inhibitor for drug transporter(s) (with no effect onclearance) resulted in an increased AUC with no change in t1/2. Inhibition ofdrug metabolizing enzyme(s) by concomitant drug(s) or auto-inactivation ofdrug metabolizing enzyme(s) by the therapeutic agent itself resulted in anincrease of both AUC and t1/2.

98


50/61

02-12-201

Figure 2. Hypothetical plot of a plasma drug concentration vs. time curve in theabsence and presence of an inducer for drug transporter(s) (with no effect onclearance) resulted in a decreased AUC with no change in t1/2. Auto-inductionof drug metabolizing enzyme(s) by the therapeutic agent itself resulted in adecrease of both AUC and t1/2. 99

100

Routes of elimination of the top 200 most prescribed drugs in 2002


51/61

02-12-201

101

Cytochrome P450 Inhibition

Drug drug interactions can occur when two drugs are coadministered and

compete for the same enzyme.

In cytochrome P450 (CYP) inhibition, one drug (perpetrator) binds to the

isozyme and the other drug (victim) is excluded from metabolism, thus

increasing to a toxic concentration.

Irreversible binding inactivates CYP and is termed mechanism-basedinhibition.

CYP inhibition can cause withdrawal from clinical use or restrictive labeling

for a drug.

102


52/61

02-12-201

103

Percentage of drugs metabolized bydifferent CYP isoformsCYP isoforms in human liver microsomes andtheir relative abundances

Summary of Important CYP IsozymesIsozyme Distribution in HLM Drugs metabolized Comments3A family 28% 50% Most abundant2D6 2% 30% Polymorphic, 5% of

white males lack isozyme2C family 1 8% 10% Polymorphic1A2 13% 4% Enzyme induction

104


53/61

02-12-201

Effects of CYP Inhibition potential risk of DDI

10 M CYP inhibition low 15% 50% inhibition @ 3 M or 3 M


54/61

02-12-201

Structure Modification Strategy

Decrease the lipophilicity (Log D 7.4) of the molecule

Add steric hindrance to the heterocycle para to the nitrogen

Add an electronic substitution (e.g., halogen) that reduces the p K a of the

nitrogen

Structure Modification Strategies to Reduce CYP Inhibition

107

Structure Modification Strategies to Reduce CYP Inhibition

108


55/61

02-12-201

109

Possible mechanisms of inhibition for the cytochrome P450s

Potential outcomes for a testcompound interacting with asubstrate-dependent drugmetabolic pathway

Examples of reversible and irreversible (arrows) CYP inhibition

110


56/61

02-12-201

Certain compounds block the cardiac K + (hERG) ion channel and induce arrhythmia.

The safety margin for hERG is IC 50 /C max unbound >30. hERG blocking might be decreased by reducing the basicity, reducing lipophilicity, and

removing oxygen H-bond acceptors

hERG Blocking

Commercial drugs that were withdrawn orhad major labeling restrictions due to hERG

blocking.

111

hERG Blocking Structure Activity Relationship

structural features that are common to binding in the hERG channel

A basic amine (positively ionizable, p K a >7.3)

Hydrophobic/lipophilic substructure(s) (ClogP >3.7)

Absence of negatively ionizable groups

Absence of oxygen H-bond acceptors

112


57/61

02-12-201

Structure Modification Strategies for hERG

Reduce the p K a (basicity) of the amine

Reduce the lipophilicity and number of substructures in the binding region

Add acid moiety

Add oxygen H-bond acceptors

Rigidify linkers

113

Toxicity remains a significant cause of attrition

during development.

Many toxic outcomes are possible, including

carcinogenicity, teratogenicity, reproductive

toxicity, cytotoxicity, and phospholipidosis.

Toxic mechanisms include reactive metabolites,

gene induction, mutagenicity, oxidative stress, and

autoimmune response.

The safety window is the concentration range

between efficacious response and toxic response.

Toxicity

114


58/61


59/61

02-12-201

Metabolic Activation-Role in Toxicity andIdiosyncratic Reactions

Types of Reactive Metabolites

Electrophiles

Acylators

Activated Double bonds

Other Electrophilic Carbon Centers

Electrophiles Localized on Nitrogen or Sulfur,

or Derived from Oxidation of SulfurRadicals

117

118

Functional group Reactive species Enzyme system

Nitro aromatics Radical CYP450/reductaseAnilines Electrophiles CYP450, peroxidasesActivated aromatics Electrophiles, radicals CYP450, peroxidasesPropionic acids Electrophiles Glucuronyl transferaseThiophenes Electrophiles CYP450Furans Electrophiles CYP450Formamides Electrophiles CYP4503-Alkyl indoles Electrophiles CYP450Thioureas Electrophiles CYP450Thioamides Electrophiles CYP450Thiazolidinones Electrophiles CYP450Cyclopropyl amines Radicals CYP450Hydrazines Radicals CYP450Acetylenes Electrophiles CYP450Sulfonylureas Electrophiles CYP450

Structural alerts, types of reactive species produced, and the enzyme system most

commonly responsible


60/61


61/61

02-12-201

Structure Modification Strategies to Improve Safety

Avoid substructures that are known to induce toxic responses

Early synthetic modifications Potentially toxic substructures should not be added to lead series

structures during lead optimization

Perform reactive metabolite assays

Structure elucidation of the metabolites or trapped intermediate

Utilize the metabolite structural modification strategies

121

eliminating the suspect functional group, blocking the potential for metabolism, making metabolism less favorable (most frequently by use of steric hindrance

or reducing oxidation potential), incorporating metabolic soft spots to direct metabolism away from the suspect

group

Strategies to minimize bioactivation risk

Documents

admet pofarm