ADMET: Absorption Mechanisms

Why do we care about mechanisms of administration? (2)

- ensuring that the drug gets to the site of action

- knowledge of transport proteins can help us improve BA in drug development, lowering doses needed to achieve therapeutic benefits

Objective

Pharmacokinetics

the study of the absorption, distribution, metabolism, and elimination of drug in or from body

- What the BODY does to the DRUG

Objective

Pharmacodynamics

describes the effects of a drug on the body

T/F: Toxicity and drug-drug interactions (DDIs) are only pharmacokinetic

FALSE

toxicity can be either pharmacokinetic (ex. inhibition of metabolism) or pharmacodynamic (ex. synergistic pharmacological effects)

Objective

What is bioavailability? BA

the fraction or percentage of the amount of drug administered that enters systemic circulation

Objective

First-pass effect

the removal of a fraction or % of drug before it reaches the systemic circulation

Enteral

- oral (PO), by mouth

- delivered via the alimentary canal

Parenteral

- non-oral
- includes administration routes such as IV/IA, IM, IT, SC

Objective

Passive diffusion is believed to be the primary mechanism of....

absorption for most drugs and biomolecules

Objective

The amount of drug absorbed is directly proportional to the magnitude of: (4)

- concentration gradient across membrane

- partition coefficient (logP) of drug

- cell/membrane surface area

- pH and pKa (for ionizable compounds)

Objective

Fick's law of diffusion equation

Flux (molecules per unit time) = (C1-C2) x Area X Permeability Coefficient/Thickness

Objective

Active transport (facilitated diffusion) is characterized by: (5)

- Requirement for energy

- Movement against an (electro) chemical gradient

- saturable kinetics

- Selectivity (in some cases)

- Competitive inhibition (drugs may act as substrates, inhibitors, or both)

Objective

T/F: In active transport, many transporters only work in one direction

FALSE

many transporters can work in either direction (import or export)

Because many transporters can work in either direction, this means these proteins are involved in....

both drug absorption and drug elimination

Objective

Many transporters are ____________ or ___________ drug targets

- existing or potential drug targets

Objective

The 2 known drug transporters in humans

- Solute carrier (SLC) protein superfamily
- ATP-binding cassette (ABC) superfanily

Objective

Solute carrier (SLC) protein superfamily

- organic anion-transporting polypeptides (OATPs)
- Proton-dependent oligopeptide transporters (POTs)

Objective

ATP-binding cassette (ABC) superfamily

- P-glycoprotein (PGP/MDR) efflux pumps

- Multidrug resistance (MRP) efflux pumps

- Breast cancer resistance protein (BCRP)