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Tansporters and Disposition of Drugs
Dr. Lu Yuan-Fu Department of Pharmacology Key Lab of Basic Pharmacology Zunyi Medical College
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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.
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Why do we need transporters?
Because drugs have to cross biological membranes and these membranes have limited permeability for drugs!
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Different modes of transport
Passive Active Facilitated = transport protein mediated!
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Three different types of transporters
(transport direction)
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The SGLT family of transporters
(SLC5A)
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The NHE family of transporters
(SLC9A) H
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Transporters and Drug Disposition
Absorption Distribution Elimination
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Transporters and Drug Disposition
ABC: ATP Binding Cassette SLC: Solute Carrier
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Drug transport in a hepatocyte
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Major ABC Transporters involved in xenobiotic disposition
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 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
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MDR1: Multidrug resistant protein
Also known as P-gp = P-glycoprotein. First member of ABC superfamily identified 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
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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.
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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.
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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
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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
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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
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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 anions Human disease: None known
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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
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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
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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
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Xenobiotic transporters of hepatocytes
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Xenobiotic transporters of hepatocytes
luminal basolateral multidrug and toxin extrusion 1 NTCP BAˉ ATP BSEP OATP1B1 OATP1B3 ATP OATP2B1 OC+ MDR1 OCT1 OC+ MATE1 OCT3 OAˉ ATP H+ OCTN2 MRP2 OAT2 OAT7
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Xenobiotic transporters in the proximal tubule
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Major SLC Transporters involved in xenobiotic disposition
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 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
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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
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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
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OCT: Organic cation transporters
SLC22A Polyspecific cation transporters Tissues: OCT1 liver (basolateral), OCT2 kidney (basolateral) Substrates: tetraethylammonium (TEA), antivirus drugs Human disease: None known
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OCTN: zwitterion/cation transporters
SLC22A Although related to the OCTs these transporters can also transport sodium OCTN1: can transport in both directions OCTN2: 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
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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
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OATP: Organic anion transporting polypeptides
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
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Xenobiotic transporters of hepatocytes
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Xenobiotic transporters in the proximal tubule
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Transporters and Drug Disposition
Distribution Transformation and Elimination Elimination Absorption Ho and Kim, Clin Pharmacol Ther. 2005
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Oxidative Stress and Formation of Adducts
BIOTRANSFORMATION Hydrophilicity Conjugates UPTAKE Nucleophiles EFFLUX Phase I Cyps Phase II Ugts, Sults Phase I Nqo1 Eh-1 Mrps Detoxification Diffusion Electrophiles Oxidative Stress and Formation of Adducts 37
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STRATEGY FOR EVALUATING DRUG-DRUG INTERACTIONS
Molecular Mechanism of enzyme induction Figure 1. Overview of the receptor-mediated mechanism of enzyme induction. (1) The inducer enters the cell via passive diffusion and or active uptake ('Phase 0'). (2) The nuclear receptors, aryl hydrocarbon receptor (AhR) and constitutive androstane receptor (CAR) are both located in the cytoplasm and pregnane X receptor (PXR) is mainly located in the nucleus. This scheme depicts Ahr and CAR-mediated pathways only; however, PXR is activated in the same manner and occurs mainly in the nucleus. (3) Once the drug binds to AhR and CAR they are translocated to the nucleus. (4) The activated receptors form heterodimers with other factors (shown in Figure 2) which bind to response elements leading to the transcription of the respective CYP isoform. (5) mRNA translocates to the cytoplasm where the translation in to CYP and other active protein occurs. Activities regulated are Phase 1 and 2 drug-metabolizing enzymes such as CYPs and conjugating enzymes, respectively, and uptake ('Phase 0') and efflux ('Phase 3') transporters. Hewitt et al Xenobiotica 2007; 37(10,11)
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STRATEGY FOR EVALUATING DRUG-DRUG INTERACTIONS
Transformation
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STRATEGY FOR EVALUATING DRUG-DRUG INTERACTIONS
Transformation blood bile Fig. 4. Inhibitory effect of CsA on OATP2-mediated uptake of [14C]CER. The inhibitory effect of CsA on the uptake of [14C]CER in MDCKII cells transfected with human OATP2 (f) or vector () was examined. Each symbol represents the mean S.E. of three independent experiments. A solid line represents the fitted line for OATP2-mediated uptake of CER. Shitara et al. Annu. Rev. Pharmacol. Toxicol :689–723
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Absorption
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Absorption P-gp or BCRP Substrate drug P-gp inhibitor (Same for BCRP)
Absorption by passive diffusion P-gp or BCRP Substrate drug P-gp inhibitor (Same for BCRP) Absorption by Active uptake
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Elimination Shitara et al. Annu. Rev. Pharmacol. Toxicol :689–723
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Major Mechanisms of drug interactions
Elimination Major Mechanisms of drug interactions Impact on renal excretion Inhibition of OCT2, OAT1 or OAT3
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Drug interaction by inhibition of renal transporters
Elimination Drug interaction by inhibition of renal transporters Shitara et al. Ann. Rev. Pharm. Tox :689–723
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Redistribution of drug from deep compartment back into plasma
Dose Deep Compartment Redistribution Shallow Compartment Plasma Elimination Plasma [D] Redistribution of drug from deep compartment back into plasma Time (hr) PTOX 917 Spring, 2010
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Distribution PTOX 917 Spring, 2010
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Distribution PTOX 917 Spring, 2010
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Distribution PTOX 917 Spring, 2010
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Proximal Tubular Cells (PTC)
Apical Side Basolateral Blood Proximal Tubular Cells (PTC) Excretion Reabsorption Oat3 Oat1 Oct1 Oct2 Oatp4c1 Mrp2 Mrp4 Bcrp Mdr1b Oat2 Octn1 Octn2 Oatp1a4 Oatp1a1 Oatp1a6 Oat5 Cnt1 Pept2 Urat1 Npt1 Asbt Ent1 Ent2 Ost Abca1 Mrp6 Oatp2b1 Oatp2a1 Oatp3a1 (+) Lumen (Filtrate) Cnt1-3 Octn1-2 Pept1-2 Ostβ Ostα Oat4 Mate1 MATE2-k (-) (-) (-) (+) (+) (+) (-) (-) (+) (+) (+) (+) (+)
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