Tansporters and Disposition of Drugs Dr. Lu Yuan-Fu Department of Pharmacology Key Lab of Basic Pharmacology Zunyi Medical College

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


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


ABCC2 Organic anion efflux, glucuronide, and glutathione conjugates


ABCC3 Organic anion efflux, glucuronide, and glutathione conjugates


ABCC4 Nucleoside transport


ABCC5 Nucleoside tranpsort


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


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


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



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


ABCC5

Is mainly a nucleoside transporter

Tissues: most tissues

Substrates: Nucleosides, cyclic nucleotides, organic anions



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


Xenobiotic transporters of hepatocytes

OATP2B1

OATP1B1

OATP1B3

NTCP

OAT7

OCTN2

OCT1

OAT2

luminalbasolateral

OAˉATP MRP2

OC+

ATP

MDR1

BAˉ

ATP

BSEP

OCT3


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


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 in the proximal tubule


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


Distribution


Distribution


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

(+)

(+)

(+)

(+)

(+)

(+)(-)

(-)

(-) (-)

(-)

(+)

(+)

Documents

Tansporters and Disposition of Drugs Dr. Lu Yuan-Fu Department of Pharmacology Key Lab of Basic Pharmacology Zunyi Medical College