Tansporters and Disposition of Drugs Dr. Lu Yuan-Fu Department of Pharmacology Key Lab of Basic...
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Transcript of Tansporters and Disposition of Drugs Dr. Lu Yuan-Fu Department of Pharmacology Key Lab of Basic...
Tansporters and Disposition of Drugs
Dr. Lu Yuan-FuDepartment of PharmacologyKey Lab of Basic PharmacologyZunyi Medical College
Introduction
DISPOSITION of a xenobiotic (drug) is the combined actions of its
ABSORPTION
DISTRIBUTION
METABOLISM (BIOTRANSFORMATION)
ELIMINATION
Transporters are involved in Absorption, Distribution and Elimination.
Why do we need transporters?Because drugs have to cross biological membranes and these
membranes have limited permeability for drugs!
Passive Active
Facilitated = transport protein mediated!
Different modes of transport
Three different types of transporters(transport direction)
The SGLT family of transporters(SLC5A)
H
The NHE family of transporters(SLC9A)
Transporters and Drug Disposition
DistributionAbsorption Elimination
Transporters and Drug Disposition
ABC: ATP Binding Cassette
SLC: Solute Carrier
Drug transport in a hepatocyte
Abbreviation Name Gene symbol
Function
MDR1/P-gp Multidrug resistant protein/ P-glycoprotein
ABCB1 Effllux from gut, brain, and placenta; biliary excretion
MDR2 Multidrug resistant protein 2 ABCB4 Phospholipid transport
BSEP Bile salt export pump ABCB11 Bile salt transport
MRP1 Multidrug resistance associated protein 1
ABCC1 Multidrug resistance in many tissues
MRP2 Multidrug resistance associated protein 2
ABCC2 Organic anion efflux, glucuronide, and glutathione conjugates
MRP3 Multidrug resistance associated protein 3
ABCC3 Organic anion efflux, glucuronide, and glutathione conjugates
MRP4 Multidrug resistance associated protein 4
ABCC4 Nucleoside transport
MRP5 Multidrug resistance associated protein 5
ABCC5 Nucleoside tranpsort
MRP6 Multidrug resistance associated protein 6
ABCC6 Unknown
BCRP Breast cancer resistance protein ABCG2 Organic anion efflux, mainly sulfate conjugates
Major ABC Transporters involved in xenobiotic disposition
MDR1: Multidrug resistant proteinAlso known as P-gp = P-glycoprotein.
First member of ABC superfamilyidentified as P-glycoprotein, was overexpressed in tumor cells and conferred multidrug resistance (MDR).
ABCB1
Tissues: intestine, liver, kidney, placenta, blood-brain barrier (apical)
Substrates: Neutral and cationic organic compounds, many commonly used drugs, numerous chemotherapeutics
Human disease: none known
MDR2: Multidrug resistant protein 2
ABCB4
Is a phospholipid flippase
Tissues: liver (apical)
Substrates: Phosphatidylcholine and some hydrophobic drugs
Human disease: Progressive familial intrahepatic cholestasis.
BSEP: Bile salt efflux pump
ABCB11
Is mainly a bile salt transporter but its function can be affected by xenobiotics
Tissues: liver (apical)
Substrates: Bile salts
Human disease: Progressive familial intrahepatic cholestasis.
MRP1: Multidrug resistance associated protein 1
ABCC1
Originally isolated from multidrug resistant cells
Tissues: Ubiquitous (basolateral)
Substrates: Glutathione and other conjugates, organic anions, numerous chemotherapeutics
Human disease: None known
MRP2: Multidrug resistance associated protein 2
ABCC2
Also known as canalicular Multispecific Organic Anion Transporter (cMOAT)
Tissues: liver, kidney, intestine (apical)
Substrates: Similar to MRP1, non-bile salt organic anions
Human disease: Dubin-Johnson Syndrome
MRP3: Multidrug resistance associated protein 3
ABCC3
Is strongly regulated e.g. under normal conditions almost absent from sinusoidal membrane of hepatocytes but up-regulated under cholestatic conditions
Tissues: pancreas, kidney, intestine, liver, adrenal glands (basolateral)
Substrates: Glucuronated and glutathione conjugates, bile salts
Human disease: None known
MRP4: Multidrug resistance associated protein 4
ABCC4
Is mainly a nucleoside transporter
Tissues: prostate, testis, ovary, intestine, pancreas, lung, liver (apical or basolateral)
Substrates: Nucleoside analogues, organic anionsHuman disease: None known
MRP5: Multidrug resistance associated protein 5
ABCC5
Is mainly a nucleoside transporter
Tissues: most tissues
Substrates: Nucleosides, cyclic nucleotides, organic anions
Human disease: None known
MRP6: Multidrug resistance associated protein 6
ABCC6
Is probably a transporter but only one substrate is known so far
Tissues: liver, kidney (basolateral)
Substrates: Anionic cyclic pentapeptide
Human disease: unknown
BCRP: Breast cancer resistance protein
ABCG2
An ABC half transporter
Tissues: placenta, intestine, breast, liver (apical)
Substrates: organic anions, numerous chemotherapeutics
Human disease: None known
Xenobiotic transporters of hepatocytes
OATP2B1
OATP1B1
OATP1B3
NTCP
OAT7
OCTN2
OCT1
OAT2
luminalbasolateral
OAˉATP MRP2
OC+
ATP
MDR1
BAˉ
ATP
BSEP
OCT3
Xenobiotic transporters of hepatocytes
multidrug and toxin extrusion 1
MATE1OC+
H+
Xenobiotic transporters in the proximal tubule
Abbreviation Name Gene symbol
Function
NTCP Sodium/taurocholate cotransporting polypeptide
SLC10A Bile salt and xenobiotic transporter
PepT Peptide transporter SLC15A Transport of di-and tri-peptides, some xenobiotics
OCT,
OCTN
Organic cation transpoter SLC22A Transport of organic cations, predominantly in kidney
OAT Organic-anion transporter SLC22A Transport of organic anions, predominantly in kidney
MATE Multidrug and toxic compound extrusion
SLC47 Transport organic cations in exchange for protons
OATPs Organic anion transporting polypeptide
SLCO Transport of organic anions, cations and neutral compounds
Major SLC Transporters involved in xenobiotic disposition
NTCP: Na+/taurocholate cotransporting polypeptide
SLC10A1
Mainly a Na+-dependent bile salt transporter
Tissues: liver, basolateral
Substrates: bile salts, estrone-3-sulfate, fluvastatin, rosuvastatin
Human disease: None known
PepT: Peptide transporter 1 and 2
SLC15A1 and SLC15A2
Proton-coupled cotransporters
Tissues: PepT1 intestine, PepT2 kidney (apical)
Substrates: di- and tripeptides, various drugs and prodrugs with peptide-like structures Human disease: None known
OCT: Organic cation transporters
SLC22A Polyspecific cation transporters
Tissues: OCT1 liver (basolateral), OCT2 kidney (basolateral)
Substrates: tetraethylammonium (TEA), antivirus drugs Human disease: None known
OCTN: zwitterion/cation transporters
SLC22A
Although related to the OCTs these transporters can also transport sodium
OCTN1: can transport in both directionsOCTN2: is a Na+/carnitine cotransporter, important for carnitine reabsorption in proximal tubule
Tissues: OCTN1: kidney, skeletal muscle, placenta, prostate, and heart; OCTN2: skeletal muscle, kidney, heart, brain, and several other tissues
Substrates: monovalent organic cations TEA, quinidine, verapamil, and the zwitterion carnitine Human disease: primary systemic carnitine
MATE: Multidrug and toxic compound extrusion
SLC47A
Polyspecific electroneutral organic cation/H+ transporters
Tissues: MATE1 predominantly liver and kidney, MATE2 predominantly kidney
Substrates: small hydrophilic organic cations similar to OCT substrates Human disease: None known
Drug Type Transporter
Rifampicin Antibiotic OATP1B1, OATP1B3
Digoxin Cardiac glycoside Oatp1a4, OATP1B3
BQ-123 Endothelin receptor antagonist
Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b2, OATP1A2, OATP1B1, OATP1B3
Enalapril ACE inhibitors Oatp1a1
Fexofenadine Antihistaminic Oatp1a1, Oatp1a4, Oatp1a5, OATP1A2
Paclitaxel(紫三醇)
Anticancer OATP1A2, OATP1B1, OATP1B3
OATP: Organic anion transporting polypeptides
Xenobiotic transporters of hepatocytes
Xenobiotic transporters in the proximal tubule
Transporters and Drug Disposition
Ho and Kim, Clin Pharmacol Ther. 2005
Absorption
Transformation and Elimination
Distribution
Elimination
UPTAKEPhase ICyps
Diffusion
BIOTRANSFORMATION
Nucleophiles EFFLUX
Det
oxi
fica
tio
n
Phase INqo1Eh-1
HydrophilicityPhase II
Ugts, Sults
ElectrophilesOxidative Stress and
Formation of Adducts
Mrps
Conjugates
Molecular Mechanism of enzyme induction
Hewitt et al Xenobiotica 2007; 37(10,11) 1196-1224
Transformation
blood bile
Shitara et al. Annu. Rev. Pharmacol. Toxicol. 2005. 45:689–723
Transformation
Absorption
P-gp or BCRP Substrate drug
P-gp inhibitor(Same for BCRP)
Absorption by Active uptake
Absorption by passive diffusion
Absorption
Shitara et al. Annu. Rev. Pharmacol. Toxicol. 2005. 45:689–723
Elimination
Major Mechanisms of drug interactions
Impact on renal excretion•Inhibition of OCT2, OAT1 or OAT3
Elimination
Drug interaction by inhibition of renal transporters
Shitara et al. Ann. Rev. Pharm. Tox 2005. 45:689–723
Elimination
PTOX 917 Spring, 2010 46
Distribution
• Redistribution
Plasma [D]
Time (hr)
Plasma Deep Compartment
Shallow Compartment
Dose
Elimination
Redistribution of drug from deep compartment
back into plasma
PTOX 917 Spring, 2010 47
Distribution
PTOX 917 Spring, 2010 48
Distribution
PTOX 917 Spring, 2010 49
Distribution
Apical SideBasolateralBasolateral
Blo
od
Proximal Tubular Cells (PTC)
Excretion Reabsorption
Oat3
Oat1
Oct1
Oct2
Oatp4c1
Mrp2
Mrp4
Bcrp
Mdr1b
Oat2
Octn1Octn2
Oatp1a4Oatp1a1
Oatp1a6
Oat5
Cnt1
Pept2
Urat1
Npt1
Asbt Ent1
Ent2
Ost
Ost
Abca1
Mrp6
Oatp2b1Oatp2a1
Oatp3a1
Apical SideBasolateralBasolateral
Blo
od
Proximal Tubular Cells (PTC)
Excretion Reabsorption
(+)
Lu
men
(F
iltr
ate
)
Blo
od
Mrp2
Mrp4
Bcrp
Mdr1b
Cnt1-3
Octn1-2Pept1-2
Oatp1a1
Asbt
Oat5
Oat2
Urat1
Ostβ
Ostα
Oat4
Mate1
MATE2-k
(+)
(+)
(+)
(+)
(+)
(+)(-)
(-)
(-) (-)
(-)
(+)
(+)