l18_pks - 20.201 Lecture#18 Page 1 20.201 Mechanisms of...

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20. 201 Lecture #1 8 10/31/05 Page 1 Lecture #1 8 : Pharmacokinetics October 31, 2005 20 .201 Mechanisms of Drug Action
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Review • Dose-response • Protein binding, drug transport(ers) • Metabolism • NOW: PHARMACOKINETICS
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20. 201 Lecture #1 8 10/31/05 Page 3 Circulatory System and Drug Distribution Image removed due to copyright restrictions. Figure by MIT OCW.
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Portal Circulation and Enterohepatic Circulation • Unique circulation of blood from gut to liver: all venous blood from stomach and intestines proceeds via portal vein directly to liver. • Poses problem for development of orally-active drugs: can achieve nearly complete removal of drug by metabolism in one pass through the liver. Figure by MIT OCW. Figure by MIT OCW. Figure by MIT OCW . Systemic Circulation Liver Portal Vein Kidney Enterocyte Small Intestine Bile Drug Metabolite Processes that decrease drug delivery to targets Processes that enhance drug delivery to targets Hepatic artery Hepatic vein Liver Bile duct Portal vein Faeces Intestines Degradation of Conjugates Drug Drug-conjugate 20. 201 Lecture #1 8 10/31/05 Page 4
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20. 201 Lecture #1 8 10/31/05 Page 5 Process by which drug leaves site of absorption and enters tissues (1) Blood flow: rate varies widely as function of tissue structure/function: Organ/Tissue Resting Blood Flow (ml/min) Ml/min/100 g Liver 1350 (27%) 95 4 360 70 3 50 25 Muscle 750 (15%) Kidney 1100 (22%) Heart 200 (4%) Skin 300 (6%) Brain 700 (14%) Bronchi 100 (2%) Other 500 (10%) (2) Capillary structure: • Most capillaries are “leaky” and do not impede diffusion of drugs • blood-brain barrier formed by high level of tight junctions between cells • BBB is impermeable to most water-soluble drugs (3) Plasma protein binding: Albumin! Distribution of Drugs
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20. 201 Lecture #1 8 10/31/05 Page 6 Classes Cell Type Products Function Size Number Lifetime Erythrocytes Erythrocytes Hemoglobin O 2 transport 7.5x2.5 um 5x10 6 /ul (M) 4x10 6 /ul (F) 120 days Leukocytes Neutrophils Oxidative chemicals Bacterial phagocytosis 15 um 5000/ul 6-7 hr blood 1-4 d tissues Granulocytes Eosinophils Inflamm. modulating chemicals Parasite defense, mod. of inflamm. 15 um 300/ul Basophils Histamine, heparin Allergic reactions 15 um 100/ul Monocytes Lysosomal enzymes Phagocytosis of viruses, protozoa, dead cells 20 um 500/ul 12-100 hr blood Mononuclear Leukocytes B-Lymphocyte Antibodies (IgG, IgM, IgE) 6-18 um 2-3000/ul T-Lymphocyte Cytokines 6-18 um Killer Cells Cytokines, etc. 6-18 um Platelets Platelets Blood clotting elements Clot formation 2-4 um 3x10 5 /ul 10 days Blood Cells
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20. 201 Lecture #1 8 10/31/05 Page 7 Molecule Mol. Wt. G/dL μ M Function Albumin 66,500 4.5 670 Chemical transport, plasma oncotic pressure Globulins ( α, β, γ ) immunoglobulins (IgG, etc.) 150,000 1.5-2 130 Humoral Immunity lipoproteins Lipid and chemical transport transferrin 79,000 0.2 17 Iron transport ceruloplasmin 150,000 0.3 20 Copper transport gluco/mucoprotein: haptoglobin Binds to hemoglobin coagulation factors (~10) Clot formation steroid-bindfing globulin 53,000 0.05 0.8 Transport of steroid hormones thyroid hormone-binding globulin Transport of thyroxine macroglobulins α 1-acid glycoprotein 42,000 0.4-1 9 Acute phase reactant, chemical
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l18_pks - 20.201 Lecture#18 Page 1 20.201 Mechanisms of...

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