Pharmacokinetics/Pharmacodynamics

Important Definitions Pharmacokinetics: Quantitative description of the time course for the disposition of a drug in the body in terms of its absorption, distribution, metabolism and elimination. Disposition: Where does the drug go? Pharmacodynamics: The study of what a drug does in the body.

Disposition or Fate of a Drug Drug at Absorption Site Drug in Body Excreted Drug Metabolite in Body Eliminated Metabolite

Disposition or Fate of a Drug Prescribed Dose Absorption Most Tissues: Nonspecific binding Protein Bound Free Drug Plasma Distribution Target Tissue: Receptor binding Elimination Metabolism Renal Excretion Effect

Routes of Drug Administration Intravenous (IV) Subcutaneous/ Intramuscular (SC/IM) Oral Rectal Inhalation

IV Administration IV Vascular Compartment Interstitial Water Cellular

SC/IM Administration SC/IM Dissolution in interstitial fluid Vascular Compartment Interstitial Water Cellular Compartment

Oral Administration Oral Vascular Compartment Interstitial Water Cellular Compartment Stomach Liver Portal circulation Duodenum

Aspirin: Where does most absorption occur? Stomach or intestine? Stomach Intestine pH =2 pH = 6

Aspirin (pKa = 3.5) COO- COO- Plasma membrane OCOCH3 OCOCH3 COOH COOH pH =2 pH = 7.4

Biliary excretion Enterohepatic circulation = Opposed elimination

Oral Administration Oral Vascular Compartment Interstitial Water Cellular Compartment Stomach Liver Portal circulation Duodenum

Factors Influencing Drug Distribution pKa, lipid solubility, molecular weight Blood flow to the tissue Binding to macromolecules, such as plasma proteins and intracellular proteins Anatomic barriers: Capillary endothelium, BBB, etc.

Biotransformation Definition: Conversion of a xenobiotic to a more water soluble compound. Biotransformation = metabolism Biotransformation is catalyzed by enzymes in the liver and other tissues.

Tissue sources of metabolizing enzymes: The liver is the richest source. Tissues associated with the major routes of exposure: skin, lung, nasal mucosa, eye, gastrointestinal tract. Others: Kidney, adrenal, pancreas, spleen, heart, brain, testis, ovary, placenta, plasma, erythrocytes, platelets, lymphocytes, aorta.

Biotransformation is accomplished by a small number of enzymes with broad substrate specificities. Some xenobiotic metabolizing enzymes also metabolize endogenous compounds. Ex: bile salts, bilirubin. Metabolizing enzymes are either: 1. Constitutive 2. Inducible – enzyme synthesis is induced by some external stimulus.

Biotransformation Reactions: Phase I: Oxidation, reduction, hydrolysis Reactions that expose or introduce a functional group. Phase II: conjugation Covalent linkage between the xenobiotic or one of its metabolites with a water-soluble, endogenous compound, e.g., glutathione.

Phase I Reactions

Phase II Conjugation

Biotransformation Reactions: Phase I: Oxidation, reduction, hydrolysis Imparts small increases in hydrophilicity. Phase II: conjugation Imparts large increases in hydrophilicity.

Inter-individual variations levels of P450’s

Examples of P450 Substrates, Inhibitors & Inducers

Other substances that can affect drug metabolism

Other substances that can affect drug metabolism

Elimination

Most important mode of elimination: Most compounds eliminated by kidneys Polar and ionic compounds eliminated more readily At what urine pH are bases absorbed? excreted?

Importance of Elimination in PK

Elimination Half-Life: t1/2 = The time required for the plasma concentration (or total body stores) of a drug to fall to half of its initial concentration.

Realistically, with repetitive dosing: Cmax [Drug] Cmin Hours after administration