INTRODUCTION₰ Toxicant (Poison) – any agent capable of producing a deleterious response in a biological system – ”Foreign” Chemicals or Xenobiotics – Air we breathe, water we drink and food we eat.
ADMEAbsorption Distribution Metabolism Excretion
Disposition of Xenobiotics Ingesti on Inhal ation Intravenous Intraperitoneal Subcutaneous absorptionGastrointestinal Lung Intramuscular tract Der mal Liver Blood and lymph Bile extracellular f at f luid distribution body Kidney Lung Secretory organs Structures soft tissue bone Bladder Alveoli excretion f eces Urine Expired Air Secretions 11
ADME: ABSORPTION₰ ability of a chemical to enter the blood (blood is in equilibrium with tissues)₰ Rate the following processes in order of fastest to slowest: ORAL INTRAVENOUS INHALATION DERMAL EXPOSURE.
INGESTION/ORAL• Most xenobiotics move through the lining of the gastrointestinal tract – Diffusion or carrier-mediated transport
Factors Affecting GI• Disintegration of dosage form and dissolution of particles• Chemical stability of chemical in gastric and intestinal juices and enzymes• Rate of gastric emptying• Motility and mixing in GI tract• Presence and type of food
INHALATION:• For gases, vapors and volatile liquids, aerosols and particles• In general: large surface area, thin barrier, high blood flow rapid absorption• Blood:air partition coefficient – influence of respiratory rate and blood flow
Airway anatomy bronchial treetrachea • diffusion distance: ~20 mm • total exchange gas exchange area: ~80 m2 16
Absorption Area in the Respiratory System Nasopharynge 5-30 µm Trachea Bronchi Bronchioles 1-5 µm Alveolar Region 1 µm 17
DERMAL• Must cross several cell layers (stratum corneum, epidermis, dermis) to reach blood vessels.• Factors important here are: lipid solubility hydration of skin site (e.g. sole of feet vs. scrotum)
INTRAVENOUS• Intraperitoneal -large surface area, vascularized, first pass effect.• Intramuscular, subcutaneous, intradermal: -absorption through endothelial pores into the circulation; blood flow is most important + other factors
ADME: DISTRIBUTION ₰ the process in which a chemical agent translocates throughout the body.• Blood carries the agent to and from its site of action, storage depots, organs of transformation, and organs of elimination
• Rate of distribution (rapid) dependent upon – blood flow – characteristics of toxicant (affinity for the tissue, and the partition coefficient)• Distribution may change over time
Storage and Binding Sites:• Storage in Adipose tissue-very lipophylic compounds (DDT) will store in fat. Rapid mobilization of the fat (starvation) can rapidly increase blood concentration• Storage in Bone--Chemicals analogous to Calcium-- Fluoride, Lead, Strontium• Binding to Plasma proteins--can displace endogenous compounds. Only free is available for adverse effects or excretion
ADME: METABOLISM• Also called as Biotransformation• The process by which the administered chemical (parent compounds) are modified by the organism by enzymatic reactions.• Bioactivation--Biotransformation can result in the formation of reactive metabolites
• 1o objective--make chemical agents more water soluble and easier to excrete – decrease lipid solubility --> decrease amount at target – increase ionization --> increase excretion rate --> decrease toxicity
₰ Occurs in liver and to some extent to; *Kidney *skin *placenta and *other organs ₰ Can have several consequences Microsomal enzyme system (MES)- a hepatic enzyme that is inducible and performs a role in biotransformation. Ex…
Hepatic biotransformation mechanisms can bemaladaptive. -”toxify” rather than “detoxify” Ex: Cigarette smoke--CarcinogenMEs evolved not to defend against the foreign chemicals but rather to metabolize endogenous substances. -Inhibitors
ADME: EXCRETION• Toxicants are eliminated from the body by several routes – Filtered thru renal corspuscle – secreted across the tubular epithelium in order to appear in urine
– Glomerular filtration- bulk flow process so that low-molecular-weight substances in plasma undergo filtration.– There is filtration of foreign chemicals except those bound to plasma proteins or RBCS.
• Urinary excretion – water soluble products are filtered out of the blood by the kidney and excreted into the urine• Exhalation – Volatile compounds are exhaled by breathing• Biliary Excretion via Fecal Excretion – Compounds can be extracted by the liver and excreted into the bile. The bile drains into the small intestine and is eliminated in the feces.• Milk Sweat Saliva