Slide 1Definitions and ADME affects on concentrationRoutes of ADMEAbsorptionCell MembraneTransmembrane TransportAbsorptionBioavailability N/ADistributionMisc. BarriersExcretionMetabolism (Biotransformation)Drug MetabolismBiotransformationSlide 15First pass effectSlide 17Slide 18Induction and InhibitionCytochrome P450 catalytic cycleSlide 21Slide 22Benzo[a]pyrene metabolismHalothane metabolismEthanol metabolismSlide 26Absorption, Distribution, Metabolism and Excretion of Toxicants. David Shubert Ph.D. [email protected] and ADME affects on concentration•Absorption – movement of a drug into the body•Distribution – spreading of the drug throughout various compartments•Metabolism – process by which a particular substance is handled in the living body (biotransformation)•Elimination – removal of the compound from the body via renal or biliary eliminationRoutes of ADMEAbsorption •Barriers–Skin, lungs, and GI tract•Cell membrane –Lipid bilayer – phospholipid heads contains polar head groups made up of (phospoatidylcholine, phosphatidylethanolamine) non polar tails made up of nonpolar lipid.•Traversing the membrane •Simple diffusion •Filtration•Facilitated diffusion•Active transport–Primary –SecondaryCell MembraneTransmembrane TransportAbsorption•Gastrointestinal Tract – Important sites for many environmental toxicants •Lungs – carbon monoxide chemical warfare chlorine, mustard gas•Skin – carbon tetrachloride can be absorbed through the skin. •Special Routes ––IP ( intraperitoneal), SQ (subcutaneous), IM (intramuscular), IV (intravenous).Bioavailability N/A•Definition - •Bioavailability = AUC oral / AUC IVDistribution •Water volume–Plasma water –blood water–Interstitial water –liquid which bathes and surrounds the cells–Intracellular water ––Extracellular water is made up of plasma water and interstitial water•Storage–Tissue -–Proteins – plasma proteins albumin warfarin is 99% plasma protein bound–Organs – protein metalothionein can bind cadmium and zinc–Fat – highly lipophilic (chlordane)–Bone - leadMisc. Barriers •Blood brain barrier – tight junction- between endothelial cells in CNS vessels•Passage across Placenta – Separates maternal from fetal circulation.Excretion •Urinary ––Glomerular filtation – free drug gets filtered out–Proximal tubular secretion – some actively secreted–Distal Tubular reabsorption – unchanged drugs may diffuse out of the kidney and escape elimination •Fecal Excretion ––Nonabsorbed ––Biliary – excreted in bile can sometimes go through reabsorption •Exhalation – •Other –Cerebrospinal fluid ––Breast Milk – more acidic than plasma (pH= 6.5)–Sweat and Saliva -Metabolism (Biotransformation)•Sites of Metabolism –Liver–Kidney–Gastrointestional tract–Lungs–Skin •The liver contains the greatest diversity and quantity of metabolic enzymes and the majority of drug metabolism occurs there.Drug Metabolism •An active drug inactive drug•An active drug active or toxic metabolite•An inactive prodrug active drug •An unexcretable drug excretable metaboliteBiotransformation •Phase I –Modify the chemical structure of a drug through oxidation, reduction, or hydrolysis–P450 system –Pro-drug system•Phase II –Conjugate drugs to large polar molecules for inactivation or enhance excretionFirst pass effect•Upon traversing the gastrointestinal epithelium, a drug is carried by the portal system to the liver before entering the systemic circulation.•One of the major differences between IV and PO administrationInduction and Inhibition•Some P450 enzymes are constitutively active–Induction (accelerated drug metabolism)•Increase rate of enzyme synthesis•Decrease rate of enzyme degradation–Example barbiturates–Inhibition•Competitive inhibition•Irreversible inhibition–Example Cimetidine (Tagamet)Cytochrome P450 catalytic cycleBenzo[a]pyrene metabolismHalothane metabolismEthanol