Drug Distribution. Joseph K. Ritter, Ph.D., Assoc. Prof. Medical Sciences Building, Room

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1 Drug Distribution Joseph K. Ritter, Ph.D., Assoc. Prof. Medical Sciences Building, Room Department of Pharmacology and Toxicology Medical College of Virginia Campus Virginia Commonwealth University Richmond, Virginia, USA Distribution refers to the passage of drugs from blood to tissues (sites of drug action, storage, metabolism, and excretion) and vice versa. Both the rate and extent of distribution are important for the time course of drug action. 1

2 The rate of distribution can determine the time to the onset of a drug response. The extent of distribution 1) relates the dose of the drug to its concentration in plasma 2) indicator of extent of distribution = volume of distribution or Vd Volume of Distribution (Vd) Pharmacokinetic variable of distribution Vd is the apparent volume that a drug distributes in to account for the observed plasma drug concentration. Units of volume (ml or L) Sometimes expressed per unit body weight (vol/kg BW) Vd is defined mathematically as the ratio of the amount of drug in the body Q to the plasma drug concentration C. Vd = Q / C 2

3 Example: Calculate the Vd of a drug when 1 gram is administered to a 70 kg person and the plasma drug level is g/l. Vd = Q/C Q = amount of drug in body (g) C = plasma drug concentration (g/liter) Vd = 1 g/0.024 g/l = 42 L Volume of distribution-water soluble drug 100 ml ungraduated beaker Mineral Oil Water What is the volume of distribution? Add 1000 mg sugar (a highly water soluble substance) and stir Take a sample of water Measure sugar conc in water Conc = 12.5 mg/ml Vd = Q/Conc = 1000mg / 12.5mg/mL = 80 ml 3

4 Volume of distribution: lipid soluble drug Mineral Oil Water Add 1000 mg of a lipid soluble drug and stir Take a sample of water Measure drug conc in water = 2 mg/ml Vd = Q/Conc = 1000mg / 2 mg/ml = 500 ml (>> volume of beaker Volume of Distribution is proportional to body weight Therefore the Vd of the example drug should ideally be expressed as L / unit body weight. Vd = 42 L/70 kg = 0.6 L/kg What would the Vd of the drug be in a 100 kg individual (their ideal body weight)? Vd = 0.6 L/kg x 100 kg = 60 L 4

5 Vd as a pharmacokinetic variable Can range from a relatively small percentage of body volume (e.g., 4.5% of total body volume) to very large volumes (>>>total body volume) Factors that determine the extent of drug distribution or Vd: -Drug characteristics -size -lipid solubility -Tissue characteristics -capillary permeability/membrane permeability -size of organs -capacity of tissue to concentrate drug -Ability of drug to bind to tissue or plasma proteins Blood flow is also an important determinant Capillary permeability The walls of capillary beds are composed of a single, endothelial cell layer (extremely thin) that is designed for effective interchange of nutrients and waste products with tissues. Unbound drugs can readily cross this layer by either filtration or passive diffusion (aided by large surface area). The rate of transcapillary movement is affected by lipid solubility (decreased lipid solubility lowers distribution rate), molecular size (increased size reduces distribution rate), and protein binding (reduces drug distribution) 5

6 Capillary permeability II Not all tissues have capillary beds with identical structures. Kidney and most other tissues have fenestrated endothelium that permits movement across the capillary wall, even if the drug has low lipophilicity - filtration or simple diffusion The brain, testes and (in pregnant women) the placenta have limited permeability to water-soluble drugs due to its endothelium having tight junctions (blood-brain barrier) lipid diffusion or carrier-mediated uptake required The liver has no endothelial cells (sinusoidal structure)-direct contact with hepatocytes in liver Membrane permeability To move inside cells within an organ or tissue, drugs have to cross cell membranes. The primary mechanism is lipid diffusion. Rate = -DAK C / X Factors affecting rate at which drugs diffuse into cells include: lipid solubility (K), drug concentration ( C), membrane area (A), molecular size (D), membrane thickness ( X), protein binding ( C) and ionization (K). 6

7 Membrane permeability II The effect of ionization state on the distribution of drugs across cell membranes is illustrated in patients with phenobarbital (PB) poisoning. (PB, weak acid, pka 7.2) These patients have metabolic acidosis (from decreased respiration) ECF ph is lowered to 7.0 or even lower (acidic). This increases the fraction of total PB in the ECF that is in the unionized state more PB enters brain cells respiration decreases even further Treatment of poisoning by barbiturates includes alkalinizing the plasma with intravenous sodium bicarbonate. Plasma protein binding Many drugs are able to bind to non-specific sites on plasma proteins: albumin (3.5-5 g/dl), others. Bound drug cannot normally undergo filtration or diffusion, only the unbound drug can leave the blood. Nature of binding: non-covalent, reversible saturable, potentially competitive Bound drug is in equilibrium with unbound (free) drug. Drug + Protein Drug Protein Bound drug can be viewed as a drug reservoir. 7

8 Plasma protein binding II The percentage of drug bound to protein in plasma varies between drugs range from low (< 1%) to high (99%) (warfarin-a blood thinner). Drugs or endogenous substances that are bound to plasma proteins may be displaced when a second drug is present that is highly protein bound. This can produce a marked increase in the plasma concentration of the free (unbound) drug. Example: infants with neonatal hyperbilirubinemia Bilirubin is highly bound to albumin. The use of sulfonamides as antibacterial agents in hyperbilirubinemic infants can displace the bilirubin encephalopathy concern. Capacity of organ to bind or concentrate drug Drugs may with high affinity and/or high capacity to non-specific sites inside cells (to proteins, lipids, etc). This binding is non-covalent, reversible. Equilibrium is formed. Total amount of drug in plasma versus tissue is determined in part by the relative affinity and number of binding sites in tissue The extent of binding to tissue constituents can be high for certain drugs (examples include chloroquine and digoxin). 8

9 Concept of drug reservoirs: drug in reservoir is in equilibrium with the drug in plasma Albumin binds various drugs and limits distribution Stomach ionizes basic drugs and traps them (ph effect) Tissues such as the liver can avidly bind drugs (chloroquine) Lipid soluble compounds can localize in fat tissue (thiopental) Certain drugs bind avidly to tissue outside the blood compartment (digoxin, Vd = 550 L/kg) Blood Flow Relatively more important for rate of distribution rather than extent Rapidly perfused (ml/100 g/min) tissues respond quickly Brain (55) Liver (20) Kidney (450) Less rapidly perfused tissues respond to drug more slowly Muscle (3) Skin (5) Poorly perfused tissues respond very slowly to drug Fat (1) 9

10 Redistribution of drugs explained by differences in organ perfusion rates % of Dose Plasma Brain Lean Fat Time (minutes) Thiopental (barbiturate used to induce anesthesia) termination of effect within min of injection due to redistribution from brain to adipose) Manipulation of blood flow to sites of injection using vasoconstrictors Some formulations of local anesthetics (procaine or lidocaine) or antiinfectives (penicillin) contain vasoconstrictor substances (epinephrine) Vasoconstrictors limit distribution of drug away from the site of injection Maintains high drug concentration at site of injection (prolongs local effect) Prolongs absorption of drug into the blood (prolongs action of drug at a site distal to the injection) 10

11 Body water compartments BODY WATER COMPARTMENTS: 50Kg & 100Kg (110 lb) (220 lb) Total body water (60% body weight) = 0.6 L/Kg, 30 L & 60 L Extracellular (20% body weight) = 0.2L/Kg, 10 L & 20 L L Plasma (4% body weight) = 0.04L/Kg, 2 L & 4 Interstitial (16% body weight) = 0.16L/Kg, 8 L & 16 L Intracellular (40% body weight) = 0.4 L/Kg, 20 L & 40 L Correspondence of body water compartments to Vd for some drugs: 4 examples Drugs with low Vd s ( L/kg) mainly restricted to plasma water (example: anticoagulant heparin) Drugs with Vds approach extracellular water (0.2 L/kg) unable to cross cell membranes to reach intracellular water space (example: highly polar, large or charged drugs such as the aminoglycoside antiinfectives) Drugs with Vds approaching total body water (alcohol) Drugs with Vds >>>total body volume concentrated in tissues outside of blood (example: the congestive heart failure drug, digoxin) 11

12 Fetal Drug Distribution Most drugs readily distribute by passive diffusion Epithelium of villi is the only major barrier Endothelium of capillaries Risks Abortion and abnormal development [Cocaine, Tamoxifen] Malformation [Thalidomide, Methotrexate, Organic Solvents] Alter behavior and intelligence [Alcohol, Cocaine, Amphetamines] Produce cancer later in life [Diethylstibesterol] Dependence/Withdrawal [Heroin, Morphine and Cocaine] Intrauterine growth retardation, prematurity, SIDS [Smoking] The End 12

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