ADME/T(ox)

1. ADME/T(ox) • Absorption • Distribution • Metabolism • Excretion • Toxicology

2. Overview - ABSORPTION Some drugs work outside the body (barrier creams, some laxatives) but most must: • enter the body: ENTERAL (entering the intestine) - oral, sublingual (under the tongue), rectal PARENTERAL - intravenous, subcutaneous, intramuscular • be transported by the blood to the target organ but note local delivery (asthma) • cross lipid barriers / cell walls: gut wall, capillary wall, cell wall, blood brain barrier ---- and reach the cellular target

3. Oral Administration

4. Advantages Generally the safest route Economical Convenient for owner No need for sterile equipment Systemic distribution Disadvantages Absorption may be variable Gastric irritation may cause vomiting Not useful if patient is vomiting Requires cooperation of patient Drug may be destroyed by gastric acidity, gut flora, mucosal enzymes, liver enzymes Onset of effect is slow Drug dilution Oral Administration

5. Factors affecting oral absorption • Disintegration of dosage form • Dissolution of particles • Chemical stability of drug • Stability of drug to enzymes • Motility and mixing in GI tract • Presence and type of food • Passage across GI tract wall • Blood flow to GI tract • Gastric emptying time

6. Intravenous Injection

7. Advantages Extremely rapid Initial absorption step is by-passed Drug levels are more accurately controlled Good for irritant drugs Suitable for large volumes Disadvantages Most dangerous route Drug must be in aqueous solution Must be performed slowly Once injected, drug cannot be removed Intravenous Injection

8. Bioavailability • the proportion of the drug in a dosage form available to the body i.v injection gives 100% bioavailability. Says nothing about effectiveness.

9. Overview - DISTRIBUTION The body is a container in which a drug is distributed - but the body is not homogeneous plasma; extracellular fluid; intracellular fluid; + special areas (fetus, brain) ----- affects concentration at site of action/elimination

10. Drug Distribution Factors • Blood Flow The rate at which a drug reaches different organs and tissues will depend on the blood flow to those regions. Equilibration is rapidly achieved with heart, lungs, liver, kidneys and brain where blood flow is high. Skin, bone, and fat equilibrate much more slowly. • Lipid Solubility Lipid solubility will affect the ability of the drug to bind to plasma proteins and to cross lipid membrane barriers. Very high lipid solubility can result in a drug initially partitioning preferentially into highly vascular lipid-rich areas. Subsequently these drugs slowly redistribute into body fat where they may remain for long periods of time.

11. Drug Distribution Factors • Capillary Permeability The capillaries in liver are extremely permeable, while those at the blood-brain barrier lie at the other extreme. Molecular size is the major factor affecting the permeability of water-soluble drugs across capillaries.

12. Overview - METABOLISM • Drug molecules are processed by enzymes evolved to cope with natural compounds • Drug may have actions increased or decreased or changed • Individual variation genetically determined • May be several routes of metabolism • May not be what terminates drug action • May take place anywhere BUT liver is prime site • Not constant - can be changed by other drugs; basic of many drug-drug interactions … metabolism is what the body does to the drug

13. Sites of biotransformation • where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and LIVER • the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation

14. Factors affecting biotransformation • age (reduced in aged patients & children) • sex (women more sensitive to ethanol) • species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); route of biotransformation can also change • Race, clinical or physiological condition

15. Biotransformation of Drugs • Phase I • Usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Often these metabolites are inactive, although in some instances activity is only modified. If Phase I metabolites are sufficiently polar, they may be readily excreted. • Phase II • Parent drugs or their Phase I metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance (glutathione, glucouronic acid, and sulfuric acid) to yield drug conjugates. In general, conjugates are polar molecules that are readily excreted and often inactive

16. Overview - EXCRETION • Urine is the main but NOT the only route. • Glomerular (kidney) filtration allows drugs <25K MW to pass into urine; reduced by plasma protein binding; only a portion of plasma is filtered. • Tubular secretion active carrier process for cations and for anions; inhibited by probenicid. • Passive re-absorption of lipid soluble drugs back into the body across the tubule cells.

17. Special aspects of excretion • lactating women in milk • little excreted in feces unless poor formulation or diarrhea • volatile agents (general anesthetics) via lungs