Pharmacokinetic Principles: ADME Flashcards
AMDE:
Absorption, Metabolism, Distribution, Excretion
ABSORPTION – Factors contributing to diffusion rate across a biological membrane:
- Passive diffusion
- Convective transport
- Carrier-mediated
- Facilitated Diffusion or Active Transport (requires ATP)
Passive diffusion rate or flux:
Fick’s Law of Diffusion
• depends on magnitude of concentration gradient across
the GI & vascular membranes (𝑪𝟏 − 𝑪𝟐) • membrane surface area
• membrane thickness
• partition coefficient of the drug

• drug diffusion coefficient
Convective transport:
- driven by pressure gradient
* e.g. glomerular filtration
Carrier-mediated (facilitated diffusion):
• lipid insoluble compounds too large to fit through
membrane pores
• transporter proteins facilitate diffusion down the concentration gradient
Active transport:
Differs from passive diffusion
- Can occur against a concentration gradient
- transporters can become saturated
- compounds with similar structures can compete for transporters
pH-partition hypothesis of drug absorption:
- The GI and other biological membranes act like lipid barriers
- Neutral form of ionizable drugs are preferentially absorbed
- Most drugs are absorbed by passive diffusion
- Absorption rate and extent are related to partition coefficient
- Weak acid and neutral drugs may be absorbed through stomach but basic drugs are not
Ionization and pH at the site of absorption:
• % ionized depends upon pKa & pH @ absorption site
• Henderson-Hasselbalch:
𝒍𝒐𝒈 (𝐩𝐫𝐨𝐭𝐨𝐧𝐚𝐭𝐞𝐝) = 𝒑𝑲𝒂 − 𝒑𝑯 (unionized)/(ionized)
for acids:
(𝐮𝐧𝐢𝐨𝐧𝐢𝐳𝐞𝐝)/(𝐢𝐨𝐧𝐢𝐳𝐞𝐝)
for bases:
(ionized)/(unionized)
Lipid Solubility & Partition Coefficient:
- Partition Coefficient describes the relative solubility of a molecule in lipid vs aqueous phase
- Most typically expressed as LogP
• Higher LogP = Higher absorption (passive membrane
diffusion)
• Regardless of lipophilicity drugs have to have some degree of aqueous solubility
Biopharmaceutics Classification System:
Class I, Class II, Class III, Class IV
FDA classifies medications in terms of solubility and permeability
Class I:
High Solubility High Permeability
Very well absorbed; fewer things can interact with them
Class II:
Low Solubility High Permeability
Issues involved deal with alteration of intestinal pH
Class III:
High Solubility Low Permeability
Problems with in terms a taking with food
Class IV:
Low Solubility Low Permeability
Few orally administered drugs
GI Transporters and Absorption (Influx):
- Influx Transporters:
- peptide transporters
- bile salt transporters
- nucleoside transporters
- OATP & OCTP
- fatty acid transporters
GI Transporters and Absorption (Efflux):
•Efflux Transporters
•P-glycoprotein (Pgp) – membrane bound
MDR protein
•MRP1; MRP2; MRP3;BCRP
Distribution – what effects absorption?
- Blood Concentration and relative blood flow to the tissues
- Local pH & degree of drug ionization
- Drug partition coefficient
- Transporters at sites of distribution
- Nature of the tissue
- adipose tissue
- CNS
- Bone
Plasma protein binding: both saturable and competitive
Protein-bound drug/free fraction at equilibrium
ONLY FREE DRUG CAN BE TRANSPORTED OR METABOLIZED
What is Metabolism?
Process of enzymatic alteration of absorbed drug to an inactive or active metabolite (metabolic inactivation or activation)
What is first-pass metabolism?
Drug concentration is greatly reduced before is reaches systemic circulation.
100% of GI absorbed drug is transported to the liver via the portal vein.
What is first-pass elimination?
- Routes not subject to Hepatic First Pass
- sublingual, transdermal, IV
- Hepatic first pass minimized by rectal administration (suppositories)
What is Elimination?
• Occurs via metabolism and excretion
• Ideally metabolism yields metabolites more water-
soluble than parent
• Kidneys principle organ for excretion of water-soluble compounds
• Drugs with MW >300 and lipophilic (polar unionized with high MW as well) more likely to be eliminated via bile
