Exam 1 - Lecture 3 & 4, Drug ADME

Lipid bilayer with protein embedded… Polar, ionized groups of molecules located on surfaces Hydrophobic, non-polar lipid side chains oriented toward inside of membrane bilayer Membrane contains aqueous channels of small diameter so permit passage only of water of small water-soluble molecules or ions Most drugs must cross membrane by diffusion through it, therefore they must dissolve in lipid layer.

Concentration gradient (Fick’s law” Lipid solubility of drug, many drugs weak acids or bases

If pH is lower than pKa -> 50% non-ionized If pH is above pKa -> 50% ionized

If pH is lower than pKa -> 50% ionized If pH is above pKa -> 50% non-ionized

Weak acids excreted faster in alkaline urine Weak bases excreted faster in acidi urine Drug diffuses across membrane, then becomes ionized and trapped so cant be reabsorbed and thus gets excreted

stomach (pH 1.9-3) small intestine (pH 7.5 -8)

log P > -5.0 = good permeation log P < -5.0 = bad permeation

requires energy, selective, saturable can operate against electrochemical gradient

no energy required cannot operate against electrochemical gradient

NET, SERT, VMAT

MDR1 ( transport xenobiotics out of cells) MRP1 ( Leukotriene secretion)

Lipid solubility and degree of ionization Dissolution rate - solubility at absorption site Concentration at site of absorption Circulation to site of absorption Area of absorptive surface Molecular size

Advantages: safest, most convenient and economical, no special devices Disadvantages: low pH or food can alter absorption are, patient compliance weak acids best absorbed in stomach (pH 1) weak bases best absorbed in intestine (pH 1-7)

special form of oral drug admin absorption across oral mucosa of certain non-ionized, lipid soluble drugs

Advantages: speed, accuracy, control, useful in emergency situations, titrate dosage, can give large volume disadvantages: no turning back, must inject slowly, risk of adverse effect from too rapid injection

Advantages: can control rate of absorption, suitable for depot-type injection, less pain than s.c., sites with highest blood flow allow fastest absorption. slow absorption from oils or other vehicles

Advantages: can control rate of absorption; suitable for insoluble suspensions, pellet implants Disadvantages: possible pain, necrosis at injection site

at mucous membranes - absorption is rapid at skin surface - most drugs not readily absorbed; proportional to lipid solubility at epidermis

absorption across pulmonary alveolar epithelium rapid access to circulation due to large surface area major means by which toxic substances enter body; allergens and environmental contaminants

injection into spinal subarachnoid space for admin to cerebrospinal axis of drugs which do not cross BBB

for high local conc of drug in certain tissue

used in experimental lab procedures, rarely used clinically

IV = 100%, most rapid onset IM = 75-100%, larger volumes more often feasible SC = 75-100%, smaller volumes than IM Oral = 5-100%, most convenient Rectal = 30 - <100%, less 1st pass than oral Inhalation = 5 - <100%, rapid onset Transdermal = 80 - <100%, used for lack of 1st pass

BBB, drug reservoirs