transport des médicaments
TRANSCRIPT
Pr Laurent Becquemont, UFR de médecineParis Sud
Transport des médicamentsTransport des médicaments
Pr Laurent Becquemont, UFR de médecineParis Sud
Pr Laurent Becquemont, UFR de médecineParis Sud
A.D.M.E.
3)Distribution
Cible (récepteurs)
2) Métabolisme (FOIE, intestin)
1) Absorption (intestin)
4) Elimination (BILE-REINS)
Pr Laurent Becquemont, UFR de médecineParis Sud
Lumière intestinale Bile Urines
Entérocytes Hépatocytes TCP
Pr Laurent Becquemont, UFR de médecineParis Sud
CYP3A4
MDR1
EFFLUX Transporters
UPTAKE Transporters
MRP2
MRP1
MRP3
MRP5
BCRP
OATPsOATPs
Pr Laurent Becquemont, UFR de médecineParis Sud
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
Pr Laurent Becquemont, UFR de médecineParis Sud
ATPATP
Drug efflux: ABCsATP Binding Cassette
Pr Laurent Becquemont, UFR de médecineParis Sud
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
Pr Laurent Becquemont, UFR de médecineParis Sud
http://bigfoot.med.unc.edu/watkinsLab/
Pr Laurent Becquemont, UFR de médecineParis Sud
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
Pr Laurent Becquemont, UFR de médecineParis Sud
Nutrition, Metabolism & Genomics GroupHead: Prof. dr. Michael Müller
Wageningen UniversityUniveristy for life [email protected]
http://nutrigene.4t.com/
Pr Laurent Becquemont, UFR de médecineParis Sud
Pr Laurent Becquemont, UFR de médecineParis Sud
Pr Laurent Becquemont, UFR de médecineParis Sud
Digoxine - P-glycoprotéineintestinale
digoxine
70 %
30 %
Pr Laurent Becquemont, UFR de médecineParis Sud
CYP3A4
CYP3A4
CYP3A4
DrugDrug+ metabolites
Drug+ metabolites
Drug+ metabolites
Drug
Drug
Drug
First pass effect
Intestinal + hepatic CYP3A4
+ P-glycoprotein
Pr Laurent Becquemont, UFR de médecineParis Sud
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
Pr Laurent Becquemont, UFR de médecineParis Sud
Pr Laurent Becquemont, UFR de médecineParis Sud
Blood
Bile
Pr Laurent Becquemont, UFR de médecineParis Sud
Pr Laurent Becquemont, UFR de médecineParis Sud
BILE
OATP
OAT
OCT
Drugs
Drugs
Drugs
Hepatic uptake of drugsBLOOD
Pr Laurent Becquemont, UFR de médecineParis Sud
OATP
OAT
OCT
Drugs
Drugs
Drugs
Hepatic uptake of drugs
Drugs
Drugs
DrugsBILE
BLOOD
Pr Laurent Becquemont, UFR de médecineParis Sud
BLOOD
ATP
MRP2
OATP
OAT
OCT
Drugs
MDR1
BCRP
ATP
ATP
Drugs
Drugs
Hepatic efflux of drugs
Drugs
Drugs
Drugs
Drugs
Drugs
Drugs
BILE
Pr Laurent Becquemont, UFR de médecineParis Sud
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
Pr Laurent Becquemont, UFR de médecineParis Sud
BILE
MDR3
Na-KATPase
Na+
K+
NTCPNa+
ATPATP
MRP3
BileAcids
Hepatic uptake of Bile acids
PC
PC
Blood
Pr Laurent Becquemont, UFR de médecineParis Sud
BILE
MDR3
Na-KATPase
Na+
K+
NTCPNa+
ATPATP
MRP3
BileAcids
Hepatic efflux of Bile acids
PC
PC
Blood
BSEPATP
Pr Laurent Becquemont, UFR de médecineParis Sud
Renal drug uptake
BasolateralOATsOATPsOCTs
Baso
late
ral
Ape
x
Urine
Pr Laurent Becquemont, UFR de médecineParis Sud
Renal drug efflux
BasolateralMDR1MRPsBCRP
Baso
late
ral
Ape
x
Urine
Pr Laurent Becquemont, UFR de médecineParis Sud