Pharmacokinetics (Drug Disposition) Drug Absorption, Distribution and Elimination General Rules Get a mental picture of what's going

on "inside". (Think about anatomy and histology in terms of "how things work.") Drugs MUST have some ability to dissolve in WATER to move around (be absorbed, reach sites of action). In almost all cases, drugs must also have a certain degree of lipid solubility to move around (leave and enter capillaries, enter and leave cells). Solubility is a preference not an absolute. "Water Soluble", "Lipid Soluble" Understand Equillibrium: Drug effects are USUALLY proportional (though not always linear) to drug concentration at the site of action. Drug concentrations in the blood stream (measured in either serum or plasma) are USUALLY proportional (and usually linear) to drug concentrations at the site of action. Drug concentration in the blood stream is ALMOST ALWAYS an excellent predictor of drug action (either efficacy or toxicity) even though they may not be identical to the concentration in the target tissue. Pharmacokinetics are the consequence of physiologic processes (that may or may not be altered by disease). "Species differences in pharmacokinetics are the PRIMARY difference between Veterinary pharmacology and Human pharmacology". Disease-induced differences are the PRIMARY difference between basic and clinical pharmacology. Do you understand proportional? linear? equillibrium? Routes of Administration (Drug Absorption) General Principles Drugs dissolve in body fluid (water). Drugs enter the circulatory system as fluid enters the circulatory system. Drugs must enter the circulatory system before they can be distributed to sights of action. (Drugs for enteric effects are an obvious exception.) Therefore, drugs are not IN the body until they are IN the bloodstream. Oral Administration Advantages Convenient, cheap, no need for sterilization, variety of dose forms (fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, mixtures) You can get the dose back if you move fast enough. Disadvantages

Variability due to physiology, feeding, disease, etc. Intractable patients First-pass effect Efficiently metabolized drugs eliminated by the liver before they reach the systemic circulation. Table 1: Location of processes involved in the absorption of oral drugs. Patient and Pharmaceutical Factors Pill compression, coatings, suspending agents, etc. GI transit time (too slow or too fast), inflammation, malabsorption syndromes Regional differences Stomach mechanical preparation "flat" absorptive surface pH extreme Rumenoreticulum stratified squamous epithelium pH varies with diet metabolism by bacterial flora significant volume of fluid compared to body water Small Intestine large absorptive surface specialized absorptive functions relatively neutral pH Colon/Rectum accessible large absorptive surface Intramuscular Administration Advantages

More consistent absorption than oral or sub-cutaneous (below) Depot or sustained effect possible (procaine penicillin G, methylprednisolone acetate, desoxycorticosterone pivalate) Administration to unconscious, vomiting or fractious patients Certainty of administration Disadvantages More difficult for owners (small patients) Pain Muscle Damage Dose cannot be recovered. Process 1. 2. 3. Drug in suspension dissolves in tissue fluid (drug in solution only has to MIX with the tissue fluid). Drug in tissue fluid solution diffuses into capillaries Drug (in solution) in capillaries is carried to circulatory system.

ANY of these processes can be "rate limiting" for absorption. Bolus injection roughly spherical water soluble vehicle mixes with tissue fluid for rapid absorption. The drug is already dissolved in "water", so dissolution in tissue fluid is not rate-limiting. Entry of drug into circulatory system limited (only) by rate of blood flow to the tissue. blood flow varies by body region/muscle group, so exercise may affect absorption rate lipid soluble vehicle The bolus remains relatively spherical. Mixing and dissolution in tissue fluid occurs from surface of bolus, so entry of drug into circulatory system limited by rate of drug "dissolution". (Movement from the "bolus" to the tissue fluid). Occasionally, vehicle may be absorbed more rapidly than drug. Then the drug "falls" out of solution in the tissue and dissolves very slowly. Produces tissue residues Reduces effect Patient and Pharmaceutical Factors Drug and vehicle solubility pH extremes Regional blood flow variability

Subcutaneous Administration Advantages Can be given by the owner (small patients) Vasoconstrictor can be added to prolong effect at site of interest Disadvantages Variability Process Much like intramuscular (though the architecture of the tissue is much different) Patient and Pharmaceutical Factors More autonomic control over blood flow (than muscle) dehydration, heat, cold, stress Topical Advantages IF systemic therapy - easy painless application (e.g., mass medication of cattle) IF skin therapy - reduced systemic effects / enhanced skin effects Disadvantages Patients groom themselves (topically applied, orally absorbed) Toxic skin reactions Variable blood flow to skin COMPLEX relationship between drug, vehicle, skin physiology Process Diffusion through stratified epithelium "Passage" through adnexal structures Patient and Pharmaceutical Factors Lipid solubility and molecule size Skin hydration and abrasion Area of application

Ambient and patient temperature Be suspicious of topical formulations from compounding pharmacies. SEE:Hoffman SB, Yoder AR, Trepanier LA. Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats. J Vet Pharmacol Ther. 2002 Jun;25(3):189-93. Vehicle effects "like" vehicles retain drug on skin surface (e.g., aqueous drug in aqueous vehicle, lipid drug in lipid vehicle) drugs in "unlike" vehicles leave the vehicle to move to skin (e.g, aqueous drug in lipid suspension, lipid drug in aqueous suspension) Intraperitoneal Advantages Larger absorptive surface area than IM / Subcutaneous Disadvantages Drugs or vehicles may cause peritonitis Damage to organs by needles Injection into organs Process Similar to subcutaneous Greater blood flow Less flow regulation Patient and Pharmaceutical Factors Generally restricted to laboratory animals Intrathecal Advantages Direct delivery to site of action Disadvantages Difficult dose calculation CSF volume is not proportional to body weight

Toxicity likely, and toxicity may be unusual Introduce infection into a VERY bad location. Process Absorption is usually by diffusion and very slow Intra-articular Advantages Direct delivery to site of action. High concentrations can be produced in the joint. Disadvantages It may be difficult to hit the joint space depending on the species (size of joint space). Difficult dose calculation Joint space volume depends on disease Recommended doses tend to be larger than necessary. Irritation of joint surfaces/capsule (chemical effects, biochemical/physiologic effects.) Introduce infection. (PSGAG - Adequan - injections now generally get "antimicrobial chaser".) Joint "flushes" don't count. Process Absorption from the site to systemic circulation is variable but often quite fast. Systemic concentrations of the drug may be produced. Effects in joint may not persist. (Drug and dose form dependent) Intra-arterial Advantages Produce extremely high concentrations "pointed at" (this is not really targeting) the tissue of interest. Used primarily for anti-tumor therapy and infectious disease therapy when blood supply is questionable. Disadvantages Dose calculation is best guess. Intra-arterial lines difficult to insert/maintain. Dosing is still really systemic. Limited number of efficacy studies (especially in animals) Process

Produce AND SUSTAIN high blood-to-tissue gradient to increase tissue concentrations of drug. Requires sustained infusion or application of tourniquet following bolus dosing. Per rectum Advantages Access to GI abosption in unconscious or vomiting patients Drug can be recovered before absorption is complete Disadvantages Animals may not willingly retain the drug Process As for oral without mechanical preparation by stomach Drug Distribution Physiologic "spaces" (Figure) Vascular space (plasma / plasma water + RBC's) There is also "tissue space" Size ~ 7% of body weight Equilibria between water and various plasma / serum proteins between ionized and unionized drug between plasma and cells Distribution in 10 to 30 minutes (mixing) Extracellular Space (exists in both vascular and tissue spaces) Size ~ 15 - 20% of body weight includes extracellular fluid in bloodstream (plasma) Equilibria between water and proteins between ionized and unionized drug

Distribution in 30 minutes to 1.5 hours Intracellular space (exists in both vascular and tissue spaces) Size ~ 35 - 45% of body weight Equilibria between ionized and unionized drug intracellular pH different (lower) than extracellular Distribution in 30 minutes to 12+ hours Reserved spaces Special barriers between plasma and tissue fluid CSF aqueous humor prostatic fluid Distribution in minutes to never Movement between spaces Vascular space (extracellular) to tissue (extracellular) space Transcytotic Endothelial junctions with inflammation Diffusion through endothelial cell membranes Carried in cells or on proteins in very special circumstances Extracellular space (of tissue) to intracellular space (of tissue) Diffusion through lipid bilayer of cells Vascular extracellular space to vascular intracellular space (drugs can move into RBCs and WBCs) Diffusion through lipid bilayer of cells WBCs may actively acquire certain drugs Diffusion limited distribution Diffusion is usually slow (relative to mixing and distribution within vascular system)

Tissue distribution of the drug controlled by the ability of the drug to diffuse into the tissue Blood flow limited distribution Diffusion can be VERY rapid Tissue distribution of the drug controlled by the rate of drug delivery to the tissue (total mg/minute) which is controlled by blood flow / gram of tissue Brain and liver concentration rise faster than muscle or fat Enterohepatic circulation How does it work? Drug or its Phase II conjugate excreted in bile Drug reabsorbed or Conjugate cleaved by bacteria and drug reabsorbed What does it mean? Elimination rate for drug is lower in spite of efficient hepatic metabolism / secretion Volume of distribution of the drug is higher Why do you care? Interrupt to improve drug elimination Insecticide poisonings, phenobarbital overdoses, etc. Figure 1: Enterohepatic circulation Mammary excretion How does it work? Non-ionic Diffusion (lipid solubility and size dependence) Inflammation reduces barriers to penetration (masititis) Ion trapping normal milk pH = 6.6 (slightly acidic versus blood). Mastitic milk pH is slightly higher Why do you care? May affect treatment of some bacterial infections of the mammary gland Nursing animals may be exposed to toxic concentrations of drug in the milk. Salivary excretion

How does it work? Non-ionic diffusion into salivary secretions Drug in saliva passes into GI tract What does it mean? Ruminants Recycle certain drugs like enteroheptic circulation (prolonged elimination) Trap certain drugs in the rumen pH dependent (enhanced elimination) Non-ruminants Little effect on elimination possible Drug Elimination Biotransformation Conversion of a drug entity to a metabolite Usually inactivates the drug generally reduces drug activity MAY activate the drug Major route of elimination for lipid soluble and protein bound drugs (because other routes are not efficient). Chemical mechanisms Oxidation, hydroxylation, hydrolysis, reduction, conjugation (acetylation, glucuronidation, sulfation, etc.) Efficiency (rate) Metabolic activity for a specific drug Blood flow to the organ Health of the organ and health of the circulatory system Organs involved Liver (most important for most drugs) Lungs (especially for autocoids) Kidneys Figure 2: Hepatic metablism

Biliary excretion Active secretion Drugs with molecular weights > 300 mostly conjugates of original drug Passive secretion Drugs with molecular weights < 300 biliary concentrations similar to plasma water Renal excretion Overall renal elimination can be a combination of three processes: (Glomerular filtration + tubular secretion) - passive reabsorption = renal elimination Figure 3: Nephron Nephron Animation Glomerular filtration passive elimination of drug dissolved in plasma water ionized and unionized NOT protein bound drug Tubular secretion energy dependent excretion by proximal kidney tubule organic acid and organic base pumps includes protein bound drugs competition between acids or between bases Passive reabsorption drug movement from renal tubule back to blood stream lipid soluble drugs unionized drug molecules normal concentrating ability Passive reabsorption can be reduced by disease (accidental) or by therapy (intentional)

increases elimination rate of the drug DOES NOT WORK if reabsorption is not an important part of normal elimination How? high urine production reduced tubular concentations of EVERYTHING reduced contact time with epithelium alter urine pH ionized drug cannot be reabosrbed acids trapped in alkaline urine bases trapped in acid urine renal elimination of aspirin can go from 2% to 30% of total elimination