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Questions and Answers
Which of the following transporters is involved in the excretion of acyl glucuronide (DF-AG) of diclofenac?
Which of the following transporters is involved in the excretion of acyl glucuronide (DF-AG) of diclofenac?
Inhibition of OAT transporters can lead to decreased clearance of penicillin.
Inhibition of OAT transporters can lead to decreased clearance of penicillin.
True (A)
What is the name of the transporter protein that is commonly affected by drugs like erythromycin and statins, leading to potential toxicity?
What is the name of the transporter protein that is commonly affected by drugs like erythromycin and statins, leading to potential toxicity?
P-glycoprotein (P-gp)
The transporter protein _____ is responsible for transporting drugs from the bloodstream into the liver cells.
The transporter protein _____ is responsible for transporting drugs from the bloodstream into the liver cells.
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Match the following transporters with their primary function:
Match the following transporters with their primary function:
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Genetic variations in OATP1B1 can lead to decreased drug uptake into the liver, resulting in higher plasma levels of statins.
Genetic variations in OATP1B1 can lead to decreased drug uptake into the liver, resulting in higher plasma levels of statins.
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What is the condition that can occur due to accumulation of cisplatin in tubular cells, potentially leading to Fanconi syndrome?
What is the condition that can occur due to accumulation of cisplatin in tubular cells, potentially leading to Fanconi syndrome?
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Which of the following plasma proteins is primarily responsible for binding acidic drugs?
Which of the following plasma proteins is primarily responsible for binding acidic drugs?
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What is the primary function of ABC transporters?
What is the primary function of ABC transporters?
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Acetazolamide decreases the distribution of salicylate into the CNS.
Acetazolamide decreases the distribution of salicylate into the CNS.
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What is the role of carrier-mediated transport in cell membranes?
What is the role of carrier-mediated transport in cell membranes?
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Acidic drugs are concentrated in the CNS due to the use of __________.
Acidic drugs are concentrated in the CNS due to the use of __________.
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Match the transporter types with their characteristics:
Match the transporter types with their characteristics:
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Which factor does NOT influence the amount of drug bound to protein?
Which factor does NOT influence the amount of drug bound to protein?
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A drug with a high fat: water partition coefficient will have minimal sequestration in fat.
A drug with a high fat: water partition coefficient will have minimal sequestration in fat.
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What is the term for the accumulation of drugs in body fat, particularly for highly lipid soluble drugs?
What is the term for the accumulation of drugs in body fat, particularly for highly lipid soluble drugs?
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Drugs like chloroquine bind to ______ in the retina, causing ocular toxicity.
Drugs like chloroquine bind to ______ in the retina, causing ocular toxicity.
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Match each drug with its characteristic accumulation site:
Match each drug with its characteristic accumulation site:
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Which of the following transporters are found on the basolateral membrane of proximal tubule cells?
Which of the following transporters are found on the basolateral membrane of proximal tubule cells?
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OCT2 is mainly expressed on the apical membrane of the kidney.
OCT2 is mainly expressed on the apical membrane of the kidney.
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Name one substrate for OAT3.
Name one substrate for OAT3.
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PEPT transporters PEPT1 and PEPT2 are members of the ________ family.
PEPT transporters PEPT1 and PEPT2 are members of the ________ family.
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Which of the following transporters is involved in proton-dependent transport?
Which of the following transporters is involved in proton-dependent transport?
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MATE transporters are responsible for the import of cationic compounds into cells.
MATE transporters are responsible for the import of cationic compounds into cells.
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What is the main role of OAT transporters in the proximal tubule?
What is the main role of OAT transporters in the proximal tubule?
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What does the acronym ADME stand for in pharmacokinetics?
What does the acronym ADME stand for in pharmacokinetics?
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Diffusion is only relevant for short-distance drug transport.
Diffusion is only relevant for short-distance drug transport.
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Which organ is primarily responsible for drug metabolism?
Which organ is primarily responsible for drug metabolism?
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The drug is passed out from the body through __________.
The drug is passed out from the body through __________.
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Match the following terms with their descriptions:
Match the following terms with their descriptions:
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Which type of diffusion is crucial for transporting large molecular weight drugs?
Which type of diffusion is crucial for transporting large molecular weight drugs?
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The blood-brain barrier has loose junctions that easily allow all substances to pass through.
The blood-brain barrier has loose junctions that easily allow all substances to pass through.
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What is the molecular weight range (in kDa) of molecules that permeate slowly through cell barriers?
What is the molecular weight range (in kDa) of molecules that permeate slowly through cell barriers?
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Which of the following is NOT a method by which small molecules cross the cell membrane?
Which of the following is NOT a method by which small molecules cross the cell membrane?
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Nonpolar molecules diffuse less readily across cell membranes compared to polar molecules.
Nonpolar molecules diffuse less readily across cell membranes compared to polar molecules.
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What are the two physiochemical factors that determine the number of molecules crossing the membrane per unit of time?
What are the two physiochemical factors that determine the number of molecules crossing the membrane per unit of time?
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Weak acids/bases exist in either ______ or ______ state depending on pH.
Weak acids/bases exist in either ______ or ______ state depending on pH.
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What type of endothelium occurs in endocrine glands to transfer hormones or molecules to the bloodstream?
What type of endothelium occurs in endocrine glands to transfer hormones or molecules to the bloodstream?
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Pinocytosis involves the trapping of small macromolecules within a vesicle created by invagination of the cell membrane.
Pinocytosis involves the trapping of small macromolecules within a vesicle created by invagination of the cell membrane.
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Match the following mechanisms of transport with their descriptions:
Match the following mechanisms of transport with their descriptions:
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Vesicle contents from pinocytosis can be released within the cell or ______ from its other side.
Vesicle contents from pinocytosis can be released within the cell or ______ from its other side.
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What is the effect of lipid solubility on drugs?
What is the effect of lipid solubility on drugs?
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What condition is crucial for rapid permeation of permeant molecules?
What condition is crucial for rapid permeation of permeant molecules?
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Flashcards
Absorption
Absorption
The process by which a drug is taken up from the site of administration into the bloodstream.
ADME
ADME
A mnemonic that stands for Absorption, Distribution, Metabolism, and Excretion.
Distribution
Distribution
The manner in which a drug spreads through the body after absorption.
Metabolism
Metabolism
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Excretion
Excretion
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Bulk flow
Bulk flow
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Diffusion
Diffusion
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Blood-brain barrier (BBB)
Blood-brain barrier (BBB)
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Acetazolamide
Acetazolamide
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Urinary Alkalization
Urinary Alkalization
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Carrier Mediated Transport
Carrier Mediated Transport
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ABC Transporters
ABC Transporters
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SLC Transporters
SLC Transporters
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Endothelium
Endothelium
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Fenestrated Endothelium
Fenestrated Endothelium
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Diffusion through Lipids
Diffusion through Lipids
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Solute Carrier (SLC)
Solute Carrier (SLC)
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Aquaporins (AQPs)
Aquaporins (AQPs)
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Pinocytosis
Pinocytosis
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Lipid Solubility
Lipid Solubility
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Ionization
Ionization
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Permeability Coefficient (P)
Permeability Coefficient (P)
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Diffusion Coefficient
Diffusion Coefficient
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OAT transporters
OAT transporters
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OAT1 function
OAT1 function
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OCT transporters
OCT transporters
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OCT1 role
OCT1 role
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PEPT transporters
PEPT transporters
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PEPT1 location
PEPT1 location
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MATE transporters
MATE transporters
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Role of transporters in liver
Role of transporters in liver
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Protein Binding
Protein Binding
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Fat Partition Coefficient
Fat Partition Coefficient
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Lipid Soluble Drugs
Lipid Soluble Drugs
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Tissue Accumulation
Tissue Accumulation
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Drug-Drug Interactions
Drug-Drug Interactions
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HMG-CoA reductase
HMG-CoA reductase
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P-gp
P-gp
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OATP1B1 polymorphism
OATP1B1 polymorphism
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Plasma protein binding
Plasma protein binding
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Cisplatin nephrotoxicity
Cisplatin nephrotoxicity
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Rhabdomyolysis
Rhabdomyolysis
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Study Notes
Absorption Basics
- Absorption is the process by which a drug is taken up from the site of administration.
- Distribution refers to where the drug travels in the body.
- Metabolism is where the drug is broken down in the body, primarily in the liver.
- Excretion is how the drug is eliminated from the body (e.g., urine, feces, bile).
How Drugs Move Around the Body
- Bulk flow: drugs are transported through the bloodstream, lymphatics, or cerebrospinal fluid. Chemical properties (hydrophobicity/hydrophilicity) don't affect this process.
- Diffusion: drugs move over short or long distances. Lipid solubility influences diffusion across hydrophobic barriers.
- Aqueous diffusion: critical for drug transport across non-aqueous barriers. This process is most important for large molecular weight (MW) drugs.
- Molecular size affects diffusion rate (the diffusion coefficient is inversely proportional to the square root of the molecular weight). Smaller molecules diffuse faster than larger ones.
- Important considerations exist for large molecules (e.g., proteins) which diffuse at a slower rate thus, a limitation in biopharmaceutical drugs.
How Drugs Cross Cell Barriers
- Single layer membranes (e.g., in the gastrointestinal (GI) tract or kidneys) have cells connected which molecules must travel through.
- Gaps between endothelial cells: These cells have a loose matrix of proteins and act as filters, allowing smaller molecules to pass easier, while large molecules and water can also pass depending on the specific tissue.
- Blood-brain barrier (BBB) and placenta have tight junctions between cells and surrounding endothelium. This barrier helps prevent harmful molecules from entering these areas
- Permeability of these barriers vary between tissues and structures (e.g. vascular endothelium).
- Other organs have endothelium that is more discontinuous.
Ways Small Molecules Cross Cell Membranes
- Direct diffusion through the lipid bilayer.
- Combination with solute carrier proteins (SLCs) or other membrane transporters.
- Diffusion through aqueous pores formed by water channels (AQPs) that traverse the lipid bilayer.
- Pinocytosis (cell drinking): used for macro molecules.
Molecules Diffusing Through Lipids
- Diffusion through aquaporins (AQPs) is important for transport of gases like carbon dioxide (CO2).
- Drugs larger than approximately 1 nanometer in diameter typically cannot diffuse directly through lipids.
- Drug distribution in patients with genetic diseases affecting AQPs is usually normal.
- Pinocytosis is a mechanism for transport of macromolecules.
Diffusing Through Lipids
- Nonpolar molecules dissolve easily in lipid membranes, diffusing across easily. Polar molecules don't dissolve in membrane lipids as easily.
- Ionized (charged) forms of weak acids and bases have limited lipid solubility.
- Permeability coefficient (P) and concentration difference across the membrane are factors determining the rate of diffusion across the membrane.
- Solubility in the membrane phase and aqueous environments influences permeability, and is expressed as the partition coefficient.
- Lipid solubility is a key factor in determining the rate of absorption from the gut, penetration into tissues, and renal elimination rate.
Ion Trapping
- Ionization and membrane permeability affect the rate at which drugs permeate membranes and their distribution between aqueous compartments.
- Lipid-soluble drugs can diffuse into cells and then be metabolized into charged metabolites, which become trapped within the cell.
- Intracellular mediators are frequently measured as an example of ion trapping.
pH Partition and Ion Trapping
- Differences in body compartments' pH can alter drug distribution and ionization. Un-ionized species cross easily while ionised species are much less able to.
- pH gradients can cause substantial concentration differences in compartments.
- Body compartments are not static but are constantly changing causing a bulk flow of drug molecules.
- In the GI tract, pH partitioning isn't the primary determinant of drug absorption; surface area of the intestine is the primary determinant.
Important Consequences of pH Partitioning
- Free base trapping can affect the effectiveness of antimalarial drugs like chloroquine by concentrating them inside the parasite's food vacuoles.
- Urine acidification accelerates excretion of weak bases and reduces excretion of weak acids, while alkalinization reverses this effect.
- Increasing plasma pH causes weak acids to move into the blood from the central nervous system (CNS)
- Reducing plasma pH causes weak bases to move into the CNS from the blood.
- Drug concentrations in the central nervous system can be affected by increasing or decreasing the pH.
Carrier-Mediated Transport
- Cell membranes have specialized transport mechanisms for molecules like sugars, amino acids, neurotransmitters, and metal ions.
- Transport is categorized as SLC (solute carrier) and ABC (ATP-binding cassette) transporters.
- SLC transporters can be passive or active. They do not use ATP.
- ABC transporters are always active pumps. They use ATP to move substances against their concentration gradient.
ABC Transporters
- ABC transporters are membrane proteins that couple substrate transport with ATP hydrolysis.
- They are involved in importing or exporting substrates.
- Different ABC transporters show different substrate specificities.
- Some ABC transporters are essential for protecting from xenobiotics and play a role in essential physiological pathways like bile transport.
- Other examples are important for drug disposition, and examples include BCRP, MDR3, MRP1.
P-glycoprotein (ABCB1)
- Another major class of ABC transporters for drug resistance.
- Important role in protecting cells from toxic substances, including some drugs.
- Expressed in many tissues, including the brain, kidneys, and intestines.
- Its roles in transport of molecules within and between compartments like the blood brain barrier (BBB) is important.
- Polymorphisms in the genes can lead to variations in transporter activity and drug response.
BSEP (ABCB11)
- Transports bile salts across the canicular membrane of hepatocytes.
- Plays a critical role in excretion of bile salts.
- Defects in transporter are associated with intrahepatic cholestasis.
MDR3 (ABCB4)
- Specific floppase for phosphatidylcholine (PC).
- Translocates phosphatidylcholine from the inner to the outer leaflet of the canicular membrane.
- Essential for maintaining bile salt micelle formation.
- Genetic mutations have been linked to various hepatobiliary diseases.
MRP1
- Multidrug resistance protein 1, an active transporter.
- Involved in excretion of a wide variety of drugs and other compounds, including those conjugated to glutathione, glucuronate, and sulphate.
- Expressed in several tissues.
MRP2
- Important transporter for the elimination of glucuronide conjugates.
- Plays a significant role in transporting drugs and metabolites from hepatocytes to bile.
- Elevated levels of bilirubin glucuronide are related to disorders like Dubin-Johnson syndrome.
BCRP (ABCG2)
- Has a similar location to P-gp, high levels of BCRP are in breast milk during lactation.
- Substrates include some drugs used in the treatment of cancer.
- Uric acid is also a substrate and levels are influenced by genetic variation resulting in gout.
SLC Transporters
- SLC transporters can be either passive (facilitative) or active which means they move substrates against their concentration gradient using energy like ATP
OATP Family
- Organic anion transporting polypeptide family.
- Plays a critical role in transporting organic anions across the sinusoidal membrane of hepatocytes.
- These proteins play a role in drug disposition.
- The most important family members are OATP1B1, OATP1B3, OATP2B1 which are responsible for drug uptake into the liver.
OAT Family
- Organic anion transporter family.
- Involved in renal excretion of organic anions.
- There are several known proteins within this family and these proteins are important for excretion of drugs.
OCT Family
- Organic cation transporters.
- Involved in drug disposition.
- OCT1 and OCT2 are the most important members, and they are involved in drug uptake in various tissues.
PEPT Family
- Peptide transporter family.
- Important for transport of peptides and other small molecules.
- These are expressed in intestines and kidneys.
- Important for drug reabsorption in kidney.
MATE Transporter Family
- Multidrug and toxin extrusion family.
- Important in transporting cations and involved in excretion via kidneys and bile.
Transporter Proteins in Liver and Kidney
- Xenobiotics are transported in and out of hepatocytes and kidneys across cell membranes.
- Some compounds are metabolized then transported.
- Compounds are also excreted by either tubular secretion or reabsorption.
Drug-Drug Interactions Involving Transporters
- Uptake, excretion or metabolism of drugs can vary as a result of inhibition from other drugs.
- Effects can be a result of a combination of drugs competing with each other or substrate/inhibitors of transporters. This can cause changes in the rate of drug absorption, metabolism, or excretion.
- Transport proteins function to distribute drugs throughout the body and determine levels in specific tissues or organs.
Pharmacogenetic Aspects of Transporters
- Genetic variations in transport proteins can affect drug responses and disposition.
- These variations can result in altered drug concentrations in certain tissues, leading to toxicity or reduced therapeutic efficacy.
- Examples include polymorphisms affecting OATP1B1 and OCT2.
Binding of Drugs to Plasma Proteins
- Most drugs bind to plasma proteins, frequently albumin.
- Important for drug distribution, metabolism, and excretion. This bound portion affects the free fraction of the drug, which is the portion that can have an effect in the body.
- The free fraction remains fairly constant even when total concentration changes.
Partition of Drugs into Fat and Other Tissues
- Fat acts as a reservoir for nonpolar drugs.
- Drugs with low water/fat partition coefficients will not accumulate in fatty tissues.
- Highly lipid soluble drugs will be stored and accumulate over time in fatty tissues. Lipid solubility can influence drug availability in other tissues (including the brain).
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Description
Test your knowledge on drug transporters, their functions, and the implications for drug clearance and toxicity. This quiz covers various transporters involved in pharmacokinetics and drug interactions. Challenge yourself with questions on specific transporter proteins and their roles in drug metabolism!
