Transport des médicaments

Pr Laurent Becquemont, UFR de médecineParis Sud

Transport des médicamentsTransport des médicaments


A.D.M.E.

3)Distribution

Cible (récepteurs)

2) Métabolisme (FOIE, intestin)

1) Absorption (intestin)

4) Elimination (BILE-REINS)


Lumière intestinale Bile Urines

Entérocytes Hépatocytes TCP


CYP3A4

MDR1

EFFLUX Transporters

UPTAKE Transporters

MRP2

MRP1

MRP3

MRP5

BCRP

OATPsOATPs


Uptake transporters

Solute carrier family (SLC)SLC10 2 isoformes (NTCP-ISBT)SLC21 6 isoformes

OATP (Organic Anion Transporting Polypeptides)-A, B, C, D, FSLC22 10 isoformes

OCT (Organic Cation Transporters) 1 à 3OCTN Novel Organic Cation Transporters) 1& 2OCTL 3 & 4OAT (Organic Anion Transporters) 1 à 3

≅ Basolatteral expression


ATPATP

Drug efflux: ABCsATP Binding Cassette


ABC ABCA 12 isoformes (ABCA1: cholesterol Tangier)ABCB 11 isoformes

MDR1 MDR3 phospatidyl-choline PFIC3, ICP BSEP: acides biliaires PFIC2

ABCC 12 isoformes MRP2 (cMOAT) (bilirubine conjuguée Dubin Johnson) MRP4 & 5 nucleosides (& analogues) CFTR: Chlore mucoviscidose

ABCD 4 isoformes (fatty acids and/or fatty acyl-CoAs ?) AdrenoleucodystrophyABCE 1 isoforme (? ?) ABCF 3 isoformes (? ?) ABCG 6 isoformes (White) (intestinal absorption / lipids-plant sterols)

ABCG2 (BCRP) (anticancéreux)

Efflux transporters

apical

apical

apical


http://bigfoot.med.unc.edu/watkinsLab/


HGNC Gene Family NomenclatureHuman ABC-Transporter Genes

The new nomenclature scheme was implemented for the human ABC and mouse Abc genes,in the human and mouse gene databases on Friday 22nd October 1999.

!! Hot Links !!New ABC scheme Approved gene names Responses ABC Nomenclature

to the proposal Committee

Guidelines for Human Mouse Nomenclature Gene Family Frequently askedGene Nomenclature Guidelines Nomenclature questions

Previous comments Dr Müller's Human 2nd FEBS Advanced Proposed nomenclature-from this page ABC- Transporter Lecture Course Abstract

Page

http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.ht


Nutrition, Metabolism & Genomics GroupHead: Prof. dr. Michael Müller

Wageningen UniversityUniveristy for life [email protected]

http://nutrigene.4t.com/


Digoxine - P-glycoprotéineintestinale

digoxine

70 %

30 %


CYP3A4

CYP3A4

CYP3A4

DrugDrug+ metabolites

Drug+ metabolites

Drug+ metabolites

Drug

Drug

Drug

First pass effect

Intestinal + hepatic CYP3A4

+ P-glycoprotein


Substrates Inhibitors Inducers

CYP3A4 Antiprotéases: Amprenavir, Saquinavir,

indinavir, Nelfinavir, Ritonavir, lopinavir,

A.calcineurine: cyclosporine, Tacrolimus

Glucocorticoides:Prednisolone,

A.arrythmiques: Quinidine, Lidocaine,

Amiodarone

Statines: Lovastatine, Simvastatine,

Atorvastatine, Cerivastatine

Anti H1: Terfenadine

Macrolides: Erythro, clarythro Rapamycin,

Inhib Calciques: Nifedipine, Nitrendipine,

Nimodipine, Amlodipine, Felodipine,

Verapamil, Diltiazem,

Benzodiazépines: Midazolam, Triazolam,

Anticancéreux: Etoposide, Ifosfamide,

Tamoxifen

Ketoconazole,

itraconazole,

Verapamil,

Ditiazem, Ritonavir,

PSC833,

Amiodarone,

Mibefradil,

Erythromycin,

clarythromycin

Grapefruit juice

Efavirenz,

Nevirapin,

Carbamazepine,

Phenobarbital,

Phenytoin,

Pioglitazone,

Rifampin,

St. John's wort,

P-gp

(MDR1)

Antiprotéases: Amprenavir, Saquinavir,

indinavir, Nelfinavir, Ritonavir

A.calcineurine: cyclosporine, Tacrolimus,

Glucocorticoides:Prednisolone, Dexamétha

A.arrythmiques: Quinidine, digoxin

Statines: Atorvastatin, Lovastatin,

Anti H1: Terfenadine, fexofenadine

Anti H2: Cimétidine, ranitidine

Macrolides: Erythromycin, Rapamycin,

Quinolones: Levoxacine, Sparfloxacine,

Inhib Calciques: diltiazem, verapamil,

Beta bloquants: Celiprolol, talinolol

Anticancéreux: (anthracyclines,taxanes….)

Loperamide, domperidone,phenytoine,

morphine

Ketoconazole,

Verapamil,

Quinidine,

Ritonavir, PSC833,

Amiodarone,

clarythromycin

Rifampin,

St John's wort


Blood

Bile


BILE

OATP

OAT

OCT

Drugs

Drugs

Drugs

Hepatic uptake of drugsBLOOD


OATP

OAT

OCT

Drugs

Drugs

Drugs

Hepatic uptake of drugs

Drugs

Drugs

DrugsBILE

BLOOD


BLOOD

ATP

MRP2

OATP

OAT

OCT

Drugs

MDR1

BCRP

ATP

ATP

Drugs

Drugs

Hepatic efflux of drugs

Drugs

Drugs

Drugs

Drugs

Drugs

Drugs

BILE


BLOOD

ATP

MRP2

OATP

OAT

OCT

Drugs

MDR1

BCRP

ATP

ATP

Drugs

Drugs

Hepatic efflux of drugs

Drugs

Drugs

Drugs

Drugs

Drugs

Drugs

BILE

DRUGS


BILE

MDR3

Na-KATPase

Na+

K+

NTCPNa+

ATPATP

MRP3

BileAcids

Hepatic uptake of Bile acids

PC

PC

Blood


BILE

MDR3

Na-KATPase

Na+

K+

NTCPNa+

ATPATP

MRP3

BileAcids

Hepatic efflux of Bile acids

PC

PC

Blood

BSEPATP


Renal drug uptake

BasolateralOATsOATPsOCTs

Baso

late

ral

Ape

x

Urine


Renal drug efflux

BasolateralMDR1MRPsBCRP

Baso

late

ral

Ape

x

Urine

Transport des médicaments

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