TOXICOCINTICA E METABOLISMO

Transporte do sitio de exposio ao sitio alvo

Exposio a Xenobitico

Absoro Distribuio Reabsoro Bioativao

Eliminao pr-sistmica Distribuio stios de armazenamento Excreo Desentoxicao

Xenobitico molcula alvo

Transporte do sitio de exposio ao sitio alvo Absoro Intestinal

Casarett & Doulls Toxicology. 6a ed, capitol 5 Fundamentos de toxicologia, Sezi Oga, 2a ediao. Cap. 1

Transporte do sitio de exposio ao sitio alvo Absoro Intestinal

Casarett & Doulls Toxicology. 6a ed, capitol 5 Fundamentos de toxicologia, Sezi Oga, 2a ediao. Cap. 1

Transporte do sitio de exposio ao sitio alvo Absoro Pela Via Respiratria

Aerossis e Partculas Slidas

Gases e Vapores

Casarett & Doulls Toxicology. 6a ed, capitol 5 Fundamentos de toxicologia, Sezi Oga, 2a ediao. Cap. 1

Transporte do sitio de exposio ao sitio alvo Transportadores de Membrana

Transportadores de Membrana Superfamlias de transportadores:
Solute Carrier (SLC) ATP-binding cassette transporters (ABC)

Absoro, Distribuio e Excreo

Transportadores no Hepatcito
Sodium Taurocholate Cotransporting Polypeptide (NTCP) Captao de sais biliares (ex. taurocolato, colato) Organic Anion Transporting Polypeptides (OATP)
Members of the SLCO family Transportam compostos aninicos ou catinicos com estrutura esteroidal ou peptdica

OATP 2B1
dehydroepiandrosterone sulfate, fexofenadine, glibenclamide Inibido por suco de laranja

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009 Lauretta M.S. Chan, Simon Lowes, Barry H. Hirst. Eur. J. Pharm. Sci. v.21, p.25-51, 2004

Transportadores no Hepatcito
Organic anions transporters (OAT)
Members of the solute carrier family SLC22A along with OCTs and OCTNs

OAT2
No utiliza contra transporte de sdio ou dicarboxilato

OAT7
Provavelmente utiliza contra transporte de sdio ou dicarboxilato Butyrate dehydroepiandrosterone sulfate and estrone sulfate

Organic Cation Transporter (OCT)

SLC22 family uptake of organic cations that are positively charged at physiological pH. Sodium independent.

OCT1

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009 Lauretta M.S. Chan, Simon Lowes, Barry H. Hirst. Eur. J. Pharm. Sci. v.21, p.25-51, 2004

Transportadores no Hepatcito
Equilibrative Nucleoside Transporters (ENT) ENT1 e ENT 2
Transportadores bidirecionais Sodium-independent Transports endogenous nucleosides and nucleoside analogs such as cancer and antiviral drugs

Concentrative Nucleoside Transporter (CNT) CNT2

Transports purines and uridine

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009 Lauretta M.S. Chan, Simon Lowes, Barry H. Hirst. Eur. J. Pharm. Sci. v.21, p.25-51, 2004

Transportadores no Hepatcito
Multidrug Resistance Proteins (P-gp)
Encoded by Mdr1a e Mdr1b genes Transport arsenic toxicants

Multidrug Resistance-Associated Proteins (MRP) MRP 2

Transporta fosfolipdios Transporta a toxina demetilfaloina do cogumelo Amanita spp

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009 Lauretta M.S. Chan, Simon Lowes, Barry H. Hirst. Eur. J. Pharm. Sci. v.21, p.25-51, 2004

Transportadores no Hepatcito
Breast Cancer Resistance Protein (BCRP) TP-Binding Cassette Subfamily G (ABCG 5, 8)
Excreo de colesterol e esterides

ATPase copper-transporting polypeptide (ATP7B)

responsible for the canalicular excretion of copper into bile

ATPase Class I Type 8B

Transporte de phosphatidylethanolamine

Bile Salt Export Pump

primarily transports conjugated bile acids

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009 Lauretta M.S. Chan, Simon Lowes, Barry H. Hirst. Eur. J. Pharm. Sci. v.21, p.25-51, 2004

Transportadores no Hepatcito
Concentrative Nucleoside Transporters (CNT) CNT1
Transporta pirimidina, adenosina e antivirais analogos (stavudina, zalcitabina, and zidovudina)

Multidrug and Toxin Extrusion Transporters (Mate) Mate 1

Efluxo de ction orgnico: Tetraetilamonio, 1-metil-4-fenilpiridinina, oxaliplatina, paraquat Contra transporte de prton

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009 Lauretta M.S. Chan, Simon Lowes, Barry H. Hirst. Eur. J. Pharm. Sci. v.21, p.25-51, 2004

Analise de Bioequivalncia Transportadores no Hepatcito

Organic Solute Transporters (OST)

Transporta ativamente sais biliares, mas tambm estrona sulfate, digoxina, e prostaglandina E2 OST e need to be co-expressed to function properly

Multidrug Resistance-Associated Proteins (MRP) MRP3, MRP4

efluxo de sais biliares

MRP6 ATP-Binding Cassette Transporter A1 (Abca1)

Effluxes cholesterol and apolipoprotein A1 in vitro

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009 Lauretta M.S. Chan, Simon Lowes, Barry H. Hirst. Eur. J. Pharm. Sci. v.21, p.25-51, 2004

Transportadores nas Clulas do Tbulo Proximal

Organic Anion Transporters (OAT) OAT 1 e OAT 3

Contra transporte de dicarboxilato

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Transportadores nas Clulas do Tbulo Proximal

Organic Cation Transporters (OCT) OCT 1, OCT2, OCT3

Transporters mediate the uptake of organic cations that are positively charged at physiological pH

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Rins Transportadores nas Clulas do Tbulo Proximal

Multidrug Resistance-Associated Proteins (MRP) MRP 2

Transporta fosfolipdios Transporta a toxina demetilfaloina do cogumelo Amanita spp

MRP4
Efluxo de cidos biliares

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Transportadores nas Clulas do Tbulo Proximal

Breast Cancer Resistance Protein BCRP

Multidrug Resistance Proteins (P-gp)

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Rins Transportadores nas Clulas do Tbulo Proximal

Multidrug and Toxin Extrusion Transporters (Mate)

Transporte aclopado a H+ Transporta Ctions Orgnicos Mate 1 Mate2-K

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Rins Transportadores nas Clulas do Tbulo Proximal

Apical sodium-dependent bile acid transporter (Asbt)

Dependente de contra transporte de sdio Preferncia por sais biliares conjugados com taurina e glicina

Concentrative Nucleoside Transporters (CNT) CNT1

Pirimidina e Adenosina Antiviral tambm so substratos: stavudina, zalcitabina, e zidovudina

CNT2
Preferencialmente Purina, mas tambm Uridina

CNT3
Purinas and pirimidinas
Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Rins Transportadores nas Clulas do Tbulo Proximal

Organic Anion Transporters (OAT) OAT 2 e OAT 4

Independente de co-transporte de sodio ou dicarboxilato independent

Peptide Transporters (Pept) Pept1 e 2

Transporta di- e tri-peptides

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Transportadores nas Clulas do Tbulo Proximal

Organic Cation/Carnitine Transporters (OCTN) OCTN 1 e 2

Transporta compostos catinicos e cartinina

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Rins Transportadores nas Clulas do Tbulo Proximal

Equilibrative Nucleoside Transporters (ENT) ENT1 e ENT 2

Transportadores bidirecionais Sodium-independent Transports endogenous nucleosides and nucleoside analogs such as cancer and antiviral drugs

Multidrug resistance-associated proteins (MRP) MRP6

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Transportadores nas Clulas do Tbulo Proximal

Organic Solute Transporters (OST)
Transporta ativamente sais biliares, mas tambm estrona sulfate, digoxina, e prostaglandina E2 OST e need to be co-expressed to function properly

ATP-Binding Cassette Transporter A1 (Abca1)

Effluxes cholesterol and apolipoprotein A1 in vitro

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

intestino Transportadores nas Clulas do Entercito

Equilibrative Nucleoside Transporters (ENT) ENT1 e ENT 2

Transportadores bidirecionais Sodium-independent Transports endogenous nucleosides and nucleoside analogs such as cancer and antiviral drugs

Organic Cation/Carnitine Transporters (OCTN) OCTN 3

Seems to function only as a carnitine transporter

Organic Cation Transporter (OCT1)

Uptake of organic cations that are positively charged at physiological pH. Sodium independent.

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

intestino Transportadores nas Clulas do Entercito

Organic Cation/Carnitine Transporters (OCTN)

OCTN1 OCTN2

Organic Cation Transporter (OCT) OCT3

Uptake of organic cations that are positively charged at physiological pH. Sodium independent.

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

intestino Transportadores nas Clulas do Entercito

Peptide Transporters (Pept) Pept1

Transporta di- e tri-peptides

Concentrative Nucleoside Transporter (CNT)

CNT1 transporta pirimidina e adenosina e anlogos antivirais (stavudina, zalcitabina, e zidovudina ) CNT2 Transporta purinas e uridina

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

intestino Transportadores nas Clulas do Entercito

Organic Anion Transporting Polypeptides OATP

Transportam compostos aninicos ou catinicos com estrutura esteroidal ou peptdica

OATP1A2 OATP 2B1

Fexofenadina, Glibenclamida Inibido por suco de laranja

Apical sodium-dependent bile acid transporter (Asbt)

Contra transporte de sdio Preferncia por sais biliares conjugados com taurina e glicina

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

intestino Transportadores nas Clulas do Entercito

Breast Cancer Resistance Protein BCRP Multidrug Resistance-Associated Proteins (MRP) MRP 2
Transporta fosfolipdios Transporta a toxina demetilfaloina do cogumelo Amanita spp

ATP-Binding Cassette Subfamily G (ABCG 5, 8)

Transportador de efluxo de esterides e colesterol

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

intestino Transportadores nas Clulas do Entercito

Multidrug Resistance Proteins (P-gp)

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

intestino Transportadores nas Clulas do Entercito

Organic Solute Transporters (OST)

Transporta ativamente sais biliares, mas tambm estrona sulfate, digoxina, e prostaglandina E2 OST e need to be co-expressed to function properly

Multidrug Resistance-Associated Proteins (MRP)

MRP3 efluxo de cidos biliares

ATP-Binding Cassette Transporter A1 (Abca1)

Effluxes cholesterol and apolipoprotein A1 in vitro

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Transportadores na Barreira Hematoenceflica

Breast Cancer Resistance Protein (BCRP) Multidrug Resistance Proteins (P-gp)

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Transportadores na Barreira Hematoenceflica

Multidrug Resistance-Associated Proteins (MRP) MRP4
Efluxo de sais biliares

MRP1

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Transportadores na Barreira Hematoenceflica

Organic Anion Transporters (OAT) OAT 3
Contra transporte de dicarboxilato

Organic Anion Transporting Polypeptides (OATP) OATP1a4

Transporta peptdeos opiides encefalina e deltorfina II e taurocolato

Curtis D. Klaassen, Lauren M. Aleksunes. Pharmacological Reviews, v.62, p.1-96. 2010 Hiroyuki Kusuhara, Yuichi Sugiyama, Drug Metab. Pharmacokinet. v.24, n.1, p.37-52. 2009

Biotransformao de Xenobiticos

Biotransformao Xenobitico

Fase I biotransformao
bioativao

Fase II biotransformao

produtos estveis

Intermedirios reativos
citotoxicidade genotoxicidade

desintoxicao

sensibilizao

reparo
necrose carcinognese teratognse hipersensibilidade

Casarett & Doulls Toxicology. 6a ed, capitol 5 Fundamentos de toxicologia, Sezi Oga, 2a ediao. Cap. 1

Biotransformao

FASE I
hidrlise oxidao reduo

FASE II
conjugao

Biotransformao
Reaes

Biotransformao
lcool desidrogenase/ aldedo desidrogenase

Casarett & Doulls Toxicology. 6a ed, capitol 6 Fundamentos de toxicologia, Sezi Oga, 2a ediao. Cap. 1

Conversion of arachidonic acid to PGH2 by prostaglandin H synthase

Casarett & Doulls Toxicology. 6a ed, capitol 6 Fundamentos de toxicologia, Sezi Oga, 2a ediao. Cap. 1

Biotransformao
prostaglandina H-sintase (PHS)

Casarett & Doulls Toxicology. 6a ed, capitol 6

Activation of acetaminophen by PHS leading to nephrotoxicity Biotransformao

prostaglandina H-sintase (PHS)

Casarett & Doulls Toxicology. 6a ed, capitol 6

Biotransformao fase II

Casarett & Doulls Toxicology. 6a ed, capitol 6

Citocromo P450 (CYP 450)

Citocromo P450 (CYP 450)

Citocromo P450 (CYP 450) Mecanismos de Catlise

R-H + O2 + NADPH2 = R-OH + H2O + NADPH+

Citocromo P450 (CYP 450)

Nomenclatura baseada na semelhana entre seqncias de aa

Super famlia
Famlia Sub-famlia Membros Individuais

Similaridade (%)
40% 55%

CYP
CYP1 CYP1A CYP1A1

CYP = Smbolo para Citocromo P450 1 = Famlia A = Sub-Famlia 1 = Membros Individuais

Citocromo P450 (CYP 450) Substratos, Indutores e Inibidores

Substratos
CYP2A6 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2E1 CYP1A2 CYP2D6 CYP3A4 cumarina nicotina bupropiona ciclofosfamida carbamazepina taxol S-warfarina tetraidrocanabinol citalopram fenobarbital acetaminofeno etanol cafeina aminas aromticas fluoxetina codeina nifedipina lidocaina

Indutores
barbituratos? fenobarbital rifampicina --rifampicina rifampicina artemisinina? etanol isoniazida omeprazol ---rifampicina fenitoina

Inibidores
pilocarpina tranilcipromina metoxiclor orfenadrina tamoxifeno R-verapamil sulfafenazol sulfiinpirazona fluconazol tranilcipromina disulfiran 4-metilpirazol fluvoxamina ciprofloxacina celecoxib quinidina cetoconazol ritonavir

Citocromo P450 (CYP 450)

Relative proportion of pharmaceuticals metabolized by the major CYP isoforms Relative concentrations of CYP isoforms in human liver

Citocromo P450 (CYP 450) Polimorfismo

Citocromo P450 (CYP 450) Diferena de fentipo devido a Polimorfismo

Citocromo P450 (CYP 450) Diferena de fentipo devido a Polimorfismo

Metabolizadores extensivos Metabolizadores lentos

Citocromo P450 (CYP 450) Polimorfismo

Citocromo P450 (CYP 450) Polimorfismo