Hydrophilicity/Lipophilicity, Bonding, and Drug-Target Interactions

passive diffusion

the major route of absorption for drugs

hydrophilicity, lipophilicity

a drug needs a balance of ______________ to absorb in the stomach or small intestines and ____________ to diffuse across the lipid bilayer

polar

Charged species will always be more ___________ and have greater water solubility (conjugate acid or base)

stomach

acid (free or conjugate) will always have major form in _____________

intestine

base (free or conjugate) will always have major form in ____________

water

solvent of choice in biological systems

dissolve

Drug must _________ in water to enter circulation and reach target tissue and be eliminated renally

polarity, lipophilicity

water solubility is positively influenced by ____________ and negatively influenced by ____________

charged

___________ drugs are more likely to be soluble in water than neutral drugs. Hence many drugs are administered as salts

ionic, hydrogen

Water solubility is positively influenced by ________ bonding and/or ________ bonding

lipid

Higher positive numbers for logP = compounds more _________ soluble

water

Higher negative numbers (more negative) for logP = compounds are more _________ soluble

LogD

LogP value at a particular pH

partition coefficient

logP

ionized

the __________ species (acid salt or protonated amine) is more polar = more water soluble

un-ionized

the ____________ species (acid or amine) is less polar = less water soluble

bonding, conformation, stereochemistry

Features of Drugs that Impact Interactions with Targets

covalent

bonds are between two atoms with similar electronegativity and electrons are shared equally

ionic

bonds are between two atoms with different electronegativity and electrons are shared unequally

target

typically, an enzyme or a receptor, has relevance to the disease state or condition to be treated

affinity

how strongly a drug interacts with its target

the lower the Kd (or Ki for antagonists) the more strongly it binds its target

Kd

drug concentration at which receptors are half-saturated

potency

how effectively a drug modulates its target

Ex: for enzyme inhibitors, the lower the effective concentration (IC50) of the drug, the more potent it is towards its target

IC50

the concentration of an inhibitor that is required for 50% inhibition of an enzyme

selectivity

the relative affinity of the drug for the target of interest compared to other targets with which it might interact (expressed as a ratio, SI)

denominator

the IC50 for the target of interest should be in the _______________ when determining SI for that target

higher

the _________ the SI, the more selective the drug will be

lower

the _________ the Kd, the higher the binding affinity