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Pharmacokinetic Principles and Drug Excretion September 7, 2007 Frank F. Vincenzi Learning objectives • Principles of active and passive permeation of membranes • Effects of lipophilicity, pH and pKa on absorption, distribution and excretion of drugs • • • • • • • Filtration Secretion Reabsorption Excretion Creatinine clearance Glomerular filtration rate probenecid Major processes of pharmacokinetic interest • Absorption • Distribution • Metabolism (also called biotransformation) • Elimination (by biotransformation &/or excretion) Drug ADME (absorption, distribution, metabolism & excretion) Permeation of drugs through membranes Specialized permeation processes for molecules across membranes (includes neurotransmitter release and recycling of membrane vesicles) Most drug absorption, distribution & excretion depends on: • • • • Surface area Blood flow pH Physico-chemical properties of the drug Fick’s law: flux (molecules/time) = (C1 - C2) * (area) *(Permeability coefficient)/(thickness) Route of administration: Surface area and blood flow affects drug absorption • Lungs - tennis court (total cardiac output) • GI tract - Intestine >> stomach (blood to portal system) • …[other routes of drug administration?] • • • • • Intramuscular (IM) (greater blood flow than) Subcutaneous (SubQ) ... Nasopharynx Eye Typical pH values of drug-absorbing membrane surfaces • • • • • • • • Gastric Duodenal Jejunal & Ileal Colon Buccal Urethral Vaginal Conjunctival 1.0 - 3.0 4.8 - 8.2 7.5 - 8.0 7.0 - 7.5 6.2 - 7.2 5.0 - 7.0 3.4 - 4.2 7.3 - 8.0 Definition of pH • -log of molar concentration of [ H+] • water, pH = 7 • 0.1 M HCl, pH = 1 (assuming complete ionization) Henderson-Hasselbach made simple: pKa - pH = log ((protonated)/(non-protonated)) When pKa = pH, then log ((50)/(50)) = log(1) = 0 • Acidic (HA and BH+) • Basic (A- and B) ratio protonated:non-prot. ratio protonated:non-prot. 1 ~ 90:10 2 ~ 99:1 3 ~ 99.9:0.1 4 ~ 99.99:0.01 -1 ~ 10:90 -2 ~ 1:99 -3 ~ 0.1:99.9 -4 ~ 0.01:99.99 Why do weak acids tend to be rapidly absorbed from the stomach? Why do weak bases tend to ‘ion trap’ in the stomach? Why, after they are given by mouth, do most drugs tend to absorb mainly from the intestine? •Fick’s law: flux (molecules/time) = (C1 - C2) * (area) *(Permeability coefficient)/(thickness) General determinants of drug distribution Useful generalizations about drug excretion: • Lipid soluble compounds tend to be metabolized to more water soluble products before being excreted (unless they are metabolized, they may not be excreted) • Water soluble compounds tend to be excreted by the kidneys (urine is mainly water) Fundamental processes in the kidney nephron: Excretion = filtration + secretion reabsorption Water filtered is about 190 liters/day; excreted is about 1.8 liters/day. About 99% reabsorption AND as water is reabsorbed the concentrations of solutes in the tubule increases…….this tends to promote passive reabsorption excretion A general rule: • Unless protein bound, most drugs are filtered by the glomerulus • If filtered, and unless reabsorbed, half of the drug in the body is eliminated by the kidneys in an hour or so. If also secreted, elimination may be faster. Creatinine clearance (CLCR) • Creatinine is a normal product of muscle metabolism. • Creatinine is filtered in the kidney glomerulus; it is neither secreted nor reabsorbed. (Well…secreted just a little) • CLCR is therefore used as a rough estimate of the glomerular filtration rate Some drugs are secreted • Penicillins • Probenecid (inhibitor of the anion pump mechanism in kidney tubules) can inhibit secretion of other compounds, for example, penicillin [it can also inhibit the reabsorption of uric acid - which is its basis in the treatment of gout] • Para-amino-hippuric acid (PAH) Most drugs are partially reabsorbed • Hydrophilic (water soluble) drugs tend to remain in tubular urine as it becomes concentrated • Lipophilic (lipid soluble) drugs tend to be reabsorbed as tubular urine is concentrated. Permeation of drugs through membranes Percent ionization of drugs at different pH values Drug X Alkaline diuresis (14 grams NaHCO3 in 1 liter, IV) increases phenobarbital (Pb, pKa = 7.2) excretion in a 70 kg human volunteer Adapted from Waddell & Butler, JCI 36: 1217-1226, 1957