Drug Transport and Excretion Notes

Drug Transport and Excretion - Lecture Notes

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Date: 11/18/2024
Course: PHMY 602
Instructor: Dr. Igor Roninson
Contact: roninsoni@cop.sc.edu
Source Material: Primary Source Section 1, Chapter 4 + this lecture

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Lecture Objectives
This lecture focuses on explaining the pharmaceutical importance of the following key topics:

  • Types of cellular drug uptake and efflux
    -ABC and SLC superfamilies of membrane transporters

  • Pathways of drug transport and excretion in the body

  • The role of membrane transporters in drug excretion in the intestine, liver, and kidney

  • The role of drug transporters in the blood-brain barrier and tissue stem cells

  • Membrane transporters in genetic diseases and pharmacogenomics

Main Topics:

I. Drug Transport at the Cellular Level
II. Drug Transport at the Organism Level

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Types of Drug Transport

Hydrophobic Transporters

  • ABC (ATP-Binding Cassette) Transporters:

    • A superfamily consisting of 49 known genes grouped into 7 families (from ABCA to ABCG).

    • Clinical drug transporters include:

      • MDR1/P-glycoprotein (ABCB1)

      • Breast cancer resistance protein (BCRP, ABCG2)

    • Important gene in genetic diseases:

      • Cystic fibrosis transmembrane conductance regulator (CFTR)

  • SLC (Solute Carrier) Transporters:

    • Superfamily comprises 315 transporters divided into 48 families.

    • They serve various functions including drug targets and play a role in drug absorption and disposition.

    • Examples:

      • SERT (Serotonin Transporter)

      • DAT (Dopamine Transporter)

      • MATE-1 and MATE-2K (Multidrug and Toxin Extrusion proteins)

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Typical Membrane Topologies for ABC and SLC Transporters

  • Nucleotide-Binding Domain (NBD): Present in ABC transporters, not in SLC transporters.

  • Characteristics of Transporters:

    • ABC transporters (also known as efflux pumps) involve energy from ATP hydrolysis.

    • SLC transporters do not use ATP for transport.

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The Major Drug Transporter

MDR1/P-glycoprotein (P-gp, ABCB1):

  • This transporter is responsible for transporting approximately half of all drugs.

  • Some notable efflux substrates include:

    • Taxol

    • Doxorubicin

    • Etoposide

    • Vincristine

    • Vinblastine

    • Actinomycin D

    • Imatinib (Gleevec)

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Active Drug Efflux by P-gp/MDR1

  • Mechanism:

    • Substrates, like Taxol, enter the cell through passive diffusion via the lipid bilayer.

    • Inhibitors: For instance, Zosuquidar can inhibit P-gp.

  • Characteristics of drugs that P-gp effluxes:

    • They do not resemble normal cellular components and cannot utilize carriers, and they often possess a hydrophobic core assisting in membrane diffusion.

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Passive Diffusion Identification in Cancer Drugs

Given the following cancer drugs, determine which is likely to enter the cell by passive diffusion:
A. Cytarabine (nucleoside analog) - Uses nucleoside transporter
B. Vincristine (tubulin binding) - Passive diffusion
C. Methotrexate (folate analog) - Uses folate transporter
D. Doxorubicin (DNA intercalating) - Passive diffusion
E. Cisplatin (DNA adduct forming) - Hydrophilic - uses copper transporter

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Membrane Transporters in Pharmacokinetic Pathways (ADME)

  • ADME: Refers to Absorption, Distribution, Metabolism, and Excretion of drugs.

  • Membrane transporters regulate:

    • The distribution and bioavailability of drugs.

    • The removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen.

    • The transport of compounds across the blood-brain barrier (BBB).

    • Protection of hematopoietic stem cells from toxins.

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Vectorial Transport: Asymmetrical Transport Across Polarized Cells

  • Basolateral Surface: Faces the blood.

  • Apical Surface: Faces the lumen.

Role of Transporters in Drug Transport in the Intestine

  • SLC Transporters:

    • Organic Anion Transporting Polypeptides (OATPs)

    • Organic Cation Transporters (OCTs)

  • ABC Transporters:

    • MDR1/P-gp (ABCB1)

    • BCRP (ABCG2)

  • Inhibition Effect:
    Inhibition of drug transporters in the intestine decreases drug excretion and increases systemic exposure in blood.

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Renal Transport/Excretion

  • Transporters:

    • P-gp, MRP (Multidrug Resistance-associated Protein) 2,4, MATE (Multidrug and Toxin Extrusion) 1, 2, 2K

    • Other transporters include Organic Cation Transporters (OCTN), Organic Anion Transporters (OAT)

  • Transport Mechanisms:

    • Active secretion through proximal tubules is the major pathway for renal elimination of drugs.

    • Transporters are localized in basolateral (blood) and apical (urine) membranes of proximal tubular epithelium.

  • Important Families of Transporters:

    • SLC superfamily: Organic Cation Transporters (OCTs), Multidrug and Toxin Extrusion (MATE)

    • ABC family: MDR1/P-gp (ABCB1), MRPs

Interaction and Inhibition

  • Inhibition of kidney transporters decreases drug excretion and increases systemic drug exposure in blood.

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Liver Transport/Excretion

  • Mechanism: Hepatocytes in the liver absorb drugs from the portal system, metabolize them, and ouput drugs into bile.

    • Fundamental metabolic reactions include oxidation, reduction, hydrolysis, and conjugation.

  • Inhibition Effects:

    • Inhibition of uptake transporters (OATP) decreases hepatic uptake leading to decreased hepatic metabolism and increased systemic exposure in blood.

    • Inhibition of efflux transporters (MDR1, BCRP) decreases biliary excretion, causing higher systemic exposure in blood (increased hepatic metabolism if drug is metabolized).

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Role of ABC Transporters in Blood-Brain Barrier (BBB)

  • ABC transporters are crucial determinants in regulating drug distribution and bioavailability at the blood-brain barrier.

  • They facilitate the removal of toxic metabolites from the brain and help in the transport of compounds across the barrier.

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ABC Transporters in Hematopoietic Stem Cells

  • Transporters such as MDR1/P-gp and ABCG2 are elevated in hematopoietic stem cells compared to other blood cells.

  • Protection Mechanism:

    • ABC transporters protect stem cells from xenobiotics through drug efflux.

  • Co-administration of Drugs:

    • If two drugs that are substrates of MDR1/P-gp or BCRP are administered together, they can compete for binding to the transporter. This leads to:

    • Increased accumulation of the target drug (object drug) in target organs (increased efficacy).

    • Increased toxicity and systemic exposure in plasma.

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Genetic Variation in Membrane Transporters

  • Genetic variations in transporters correlate with genetic diseases and individual differences in drug response.

  • SLC Transporters:

    • Involved in Mendelian diseases, 84 SLC transporters are implicated.

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ABC Transporter and Cystic Fibrosis

  • Cystic Fibrosis Transduction Regulator (CFTR):

    • An ATP-gated chloride and anion channel.

    • Mutations in CFTR lead to dysregulation of epithelial fluid transport affecting lungs, pancreas, and other organs.

    • The common mutation (ΔF508) results in failure of the synthesized protein to reach the membrane due to defect in the chloride channel function.

    • Epidemiology:

    • 1 in 25 individuals of Northern European ancestry carries CFTR mutations (autosomal recessive disease prevalence is 1 in 3000).

  • Genetic Variants and Drug Response:

    • Various transporter genes affect drug response, influencing concentrations and effects of numerous drugs.

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Importance of Understanding Membrane Transporters for Clinical Practice

  • Understanding transporters is crucial due to their influence on drug efficacy and toxicity, as follows:

    • A: New drug candidates might not reach target organs effectively due to transportation issues.

    • B: Patients may have differing responses to the same drugs based on transporter expression variances or genetic differences.

    • C: Drugs that interact with transporters may have positive or negative effects on other drugs utilizing the same transporters.

    • D: Transporters represent a major class of new drug targets aimed to enhance pharmacokinetics.

    • Conclusion: Overall, awareness of transporter-related dynamics is essential for optimizing therapeutic strategies and individualizing patient care.