ADME: absorption, distribution, metabolism, and elimination of drugs

volume of distribution

large #: lipophilic

small #: hydrophilic

what is absorption

movement of drug from site of application into the bloodstream or target tissue

what is distribution

movement of drug from blood to target site of action OR from one location in the body to another

what is metabolism

transformation of the drug, usually with the aid of an enzyme, detoxification of drug, or possible bioactivation

what is bioactivation

activation of prodrug into drug by enzyme in patient

what is elimination/excretion

elimination of the drug from the body

what is the major bioactivation reaction type

hydrolysis of esters

where does absorption occur/drug enter the blood stream

hepatic portal vein

what is the prime site of metabolism/site of first pass metabolism

liver

what is bioavailability

how much of the drug is administered vs. how much of the drug makes it into systemic circulation

what can an unbound drug do after absorption

travel to sites of action, be stored in tissues (fats), bind plasma proteins, go through metabolism, go through elimination/excretion

how much of a drug gets destroyed in the liver during first pass metabolism

5-88% of the drug

characteristics of highly plasma protein bound drugs

-long acting (drug can unbind PP and become UD)

-long half lives

-metabolize at slow rates

considerations of drug absorption

-physiochemical property of drug (aqueous/lipid solubility, pKa, molecular weight, stability)

-systemic v local effects

-invasive v noninvasive

-first pass effect (oral dosing)

-bioavailability

common routes of drug administration

-parenteral (IV, IM, subq)

-oral

-sublingual/buccal

-inhalation

-topical

-rectal

-nasal

what does rate of absorption depend on

% nonionized drug at a given pH

colon efflux pump

p-glycoprotein

what does ionization states being in equillibrium mean

-even if it is predominantly ionized, there is still a % that is non-ionized, and once that % is absorbed, the equilibrium will be reestablished

-the percentage of each species is constant at a given pH value

what ways can a drug be eliminated from the body

renal (kidneys), hepatic (liver/biliary excretion), pulmonary (lungs)

how can quantification of drug elimination be accomplished

using half-lives and clearance expressions

what is the MAIN route of drug elimination

renal excretion

mechanisms of renal excretion

filtration, active tubular secretion, tubular reabsorption

physiochemical determinants of renal excretion

molecular size (<5000), lipophilicity (LogP), ionization (urine pH: 5-8), protein binding

threshold of tubular reabsorption

% nonionized with a threshold of greater than or equal to 30% nonionized

overall rate of drug renal excretion is controlled by

physiochemical properties, pH of urine, GFR (glomerular filtration rate)

renal elimination and water solubility is determined by

% ionized

enterohepatic recycling

drug enters liver is secreted into bile and transported back to the small intestine, then reabsorbed into the blood stream

hepatic v renal elimination

hepatic: MW >300 g/mol, high logP

renal: <300 g/mol, low logP

excretion in breast milk

-breast milk has pH of 7.0

-pH is lower than plasma, so trapping can occur

-higher concentration of drug in milk than plasma

-means feeding baby can consume the drug

a drug must be in what state to maximize elimination

ionized

a drug must be in what state to maximize reabsorption

non-ionized