Absorption, Distribution, Metabolism and Elimination

(ADME)

Drug Absorption

• Dependant on route, MW (size), solubility, availability of carrier molecules, etc.

• Wide variation in rate among different genetic backgrounds, and specific cases (ex.- percutaneous absorption through abraded skin).

• Greatly affects how quickly a drug elicits its biological response.

Routes of Absorption

• Most common routes include:– Topical (influenced by blood flow, dermal

thickness, lipid solubility)– Oral (dependant on pH, solubility, formulation,

stability)– Rectal (wide variation in absorption, but useful

in comatose patients, or if drug is easily destroyed by GI pH or digestive enzymes)

– Pulmonary (rapid absorption of many compounds, also for local treatment)

Routes of Absorption

• Parenteral– Subcutaneous (under dermis, nonirritating

drugs only, slow absorption)– Intramuscular (into muscle, nonirritating only,

faster absorption, depot injections)– Intravenous (into vein, irritating drugs OK if

given slowly, instant absorption)– Intra-arterial (into artery, good for local

therapy)– Intrathecal (into CSF, bypassing BBB)

GI Absorption Curve

Absorption vs. Route

Membrane Permeability to Drugs

Membrane Permeability Based on Water Solubility

Permeability vs. Lipid Solubility

Absorption vs. Lipid Solubility

Intestinal Permeability Barrier

Diffusion vs. Partition Coefficient

pH vs. Absorption

Absorption via Endocytosis

Absorption via Gap Junctions

Tight Junctions

Capillary Permeability

Fenestrated Capillaries

CSF/Plasma Equilibrium

Lung Permeability

Tissue Permeability Summary

Distribution

• Phase following absorption.

• Describes how a drug gets to it’s target tissue for action.

• Influenced by solubility, body water, protein binding, tissue binding, specific carriers.

Distribution

• Total body water (easily accessible)– Intracellular ~ 40%– Extracellular ~ 20%

• Interstitial ~ 15%• Vascular ~ 5%

• Remainder in body fluids, bone, tendons, etc.

Disposition Pathways

Apparent Volume of Distribution

Protein Binding vs. Disposition

ADME Following IV Dosing

IV Bolus Distribution

Perfusion Rate vs. Distribution

Redistribution of Halothane

Metabolism and Elimination

• How a drug gets removed (or changed) from body.

• Most drugs metabolized to some degree.

• Prodrugs utilize metabolism to form active compounds.

• Two primary types of metabolism– Phase 1 (breakdown)– Phase 2 (synthetic)

Metabolism and Elimination

• Metabolic Locations:– Liver– Lungs– Skin– Kidney– Blood– Most all other tissues to a small degree

Drug Disappearance Curve

Biotransformation Reactions

Metabolic Enzymes

Phenytoin Metabolism

Cytochrome P-450 (CYP)

Cytochrome P-450 (CYP) Reactions

Reduction Reaction

Phase 2 Glucuronidation

Phase 2 Glutathione Conjugation

Phase 2 Sulfate Conjugation

Miscellaneous Phase 2 Reactions

Nonmicrosomal Hydrolysis