Drug Absorption and Distribution Notes

Overview of Session

  • Focus on drug absorption and distribution, including:
    • Drug penetration into cells
    • Carrier-mediated transport
    • Solute Carrier (SLC) transporter family
    • ATP-binding Cassette (ABC) transporter family
    • Concept of body compartments:
    • Plasma protein binding
    • Partitioning into tissues
    • Blood-brain barrier (BBB)
    • Volume of distribution and specialized delivery systems.

Routes of Drug Penetration into Cells

  • Major pathways for drug entry:
    • Diffusion through lipid membrane:
    • Predominant for lipophilic drugs.
    • Diffusion through aqueous channels:
    • Many drugs are too large to use this route.
    • Carrier-mediated transport:
    • Essential for hydrophilic drugs.
    • Pinocytosis:
    • Example: Transport of insulin into the brain.

Carrier-Mediated Transport

  • Cell membranes possess specialized transport mechanisms that:
    • Regulate influx (entry) and efflux (exit) of key molecules (e.g. glucose).
  • Two primary types of transporters:
    • SLC transporters:
    • Mediate passive transport down electrochemical gradients.
    • ABC transporters:
    • Mediate active transport against gradients (ATP-driven).
  • Over 350 transporters are known; many drugs are substrates.

SLC Transporter Family

  • Characterization:
    • Superfamily that regulates cellular uptake and disposal of nutrients and chemicals.
    • Second largest group of membrane proteins after GPCRs.
    • Divided into 48 families, each with distinct endogenous substrates:
    • SLC2: Sugar transporters.
    • SLC6: Neurotransmitter transporters.
    • SLC43: L-amino acid transporters.
  • Involvement in transporting therapeutic drugs (e.g., OATP1B1 facilitating simvastatin uptake into hepatocytes).

Importance of Organic Cation and Anion Transporters (OCTs and OATs)

  • Functionality:
    • Transfer cations and anions across membranes.
    • Ubiquitous expression in several key sites:
    • Blood-brain barrier, gastrointestinal tract, renal tubules, biliary tract.
  • Examples:
    • OCT1: Transports metformin, desipramine.
    • OCT2: Transports cisplatin, leading to nephrotoxicity.
    • OATs: Transport NSAIDs, cimetidine, etc.

ABC Transporter Family

  • Characterization:
    • Comprises ~50 transport proteins mainly involved in efflux of toxins and xenobiotics from cells.
  • Key transporters include:
    • MRP1 (ABCC1) and BCRP (ABCG2).
    • P-glycoprotein (ABCB1):
    • Discovered in the 1970s; associated with drug resistance in cancer.
    • Highly expressed at blood-tissue barriers like BBB and in liver, kidney, and GI tract.
    • Acts as an active transporter, expelling substrates against gradients.

Importance of ABC Transporters

  • Protective Mechanism:
    • Inducible expression serves a protective role against toxins.
  • Characteristics of substrates:
    • Mostly planar, lipid-soluble drugs. Common examples include:
    • Digoxin: Serum concentration reflects P-gp function.
    • Loperamide: Limited BBB penetration.
    • Ivermectin: Neurotoxic effects in certain dog breeds.

Genetic Variation in Drug Transporters

  • Genetic variants can influence drug metabolism and pharmacokinetics:
    • OCT1 Variants: Affect glucose levels following metformin treatment.
    • ABCB1 Variants: Impact pharmacokinetic profiles (C_max and AUC) of drugs like digoxin.

Summary of Drug Transport Mechanisms

  • Drug classes:
    • Most drugs are lipophilic and permeate membranes by passive diffusion.
    • Carrier-mediated transport is essential for hydrophilic drugs.
  • Role of transporters:
    • SLCs: Involved in both influx and efflux of drugs.
    • ABCs: Primarily facilitate efflux (protective properties).
  • Key drug substrates exhibit overlapping specificities.

Distribution of Drugs in the Body

  • Body Water Compartments:
    • Four main compartments:
    • Plasma water
    • Interstitial water
    • Intracellular water
    • Transcellular water (e.g., CSF, fetal circulation).
  • Drug existence in these compartments:
    • Both free and bound forms, ionized and non-ionized species.
    • Factors affecting distribution:
    • Lipid solubility
    • Protein binding
    • pH partition
    • Fat:water partition.

Plasma Protein Binding

  • Binding Dynamics:
    • At therapeutic concentrations, many drugs bind to plasma proteins:
    • Albumin: Major protein binding neutral and acidic drugs (e.g., warfarin).
    • α1-acid glycoprotein: Binds basic drugs (e.g., quinine).
  • Binding Characteristics:
    • Only free drug is pharmacologically active.
    • Degree of binding influenced by:
    • Free drug concentration
    • Affinity for binding sites
    • Protein concentration.
  • Binding capacity can create a drug depot and affect pharmacokinetics (e.g., diazepam, phenylbutazone).

Partitioning into Tissues

  • Adipose Tissue:
    • Significant for lipid-soluble drugs acting as a depot.
    • Drugs can accumulate based on fat:water partition coefficients:
    • Morphine (partition coefficient 0.4) vs. Thiopental (coefficient 10).
    • Importance of equilibration time and chronic usage effects:
    • Chronic use can lead to significant accumulation of lipid-soluble drugs (e.g., benzodiazepines).
    • Specific affinities noted in compounds like chloroquine (retina accumulation) and tetracyclines (bone and teeth accumulation).

Blood-Brain Barrier (BBB)

  • Characteristics:
    • Concept initiated by Paul Ehrlich (blue dye injection).
    • Protects brain from most (85%) drugs; requires high lipid solubility.
    • Compromised under specific conditions (e.g., brain infections).
  • Anatomical Features:
    • Continuous endothelium with tight junctions, basal membrane, low fenestrations, high metabolic rate, presence of drug transporters.

Volume of Distribution (Vd)

  • Definition:
    • Volume of distribution represents fluid volume needed to contain the total drug amount (Q) at plasma concentration (Cp): V</em>d(L)=Q(mg)Cp(mg/L)V</em>d (L) = \frac{Q (mg)}{C_p (mg/L)}
  • Drug Class Examples:
    • Large molecules (e.g., heparin) primarily confined to plasma (Vd≈0.05L/kgV_d \approx 0.05 L/kg).
    • Polar drugs (e.g., gentamicin) with Vd≈0.2L/kgV_d \approx 0.2 L/kg.
    • Lipid-soluble drugs (e.g., phenytoin) distribute across body water ($V_d = 0.55 L/kg$).
    • Highly lipid-soluble drugs (e.g., chloroquine) can have $V_d$ values exceeding total body water (~$200 L/kg$).

Specialized Drug Delivery Systems

  • Innovations in drug delivery aim to optimize absorption and targeted distribution:
    • Nanoparticles: Biodegradable polymers carrying drugs.
    • Pro-drugs: Examples include levodopa and zidovudine.
    • Antibody-drug conjugates: Target therapies using tumor-specific antigens.
    • Liposomes: Phospholipid vesicles for non-lipid soluble drugs.
    • Coated implantable devices: Structures designed for localized drug release (e.g., drug-releasing stents).

Summary of Distribution and Drug Delivery

  • Drugs are distributed across body compartments, with plasma protein binding influencing the crossing of cell membranes.
  • ~85% of drugs do not penetrate the BBB effectively.
  • Volume of distribution provides insight into the degree of a drug's tissue distribution.