Pharmacokinetics Module 4 - ADME

Absorption

the route a drug takes to reach the blood plasma

Drug must cross multiple polar membranes to reach its target site

Each side of a membrane has it's own proteins expression, particularly transport proteins

Dependent on

lipophilicity

partisan coefficient

Kd= [drugs] in lipid / [drugs] in aqueous

Kd= k1/ k2

K1= rate from water to oil

K2= rate from oil to water

this is a ratio, the higher it is the easier it is for the drug to get into the lipid membrane

Say 10:1

will move 10 times faster into lipid than into water

10 times more lipophilic

K1 is 10 times faster than k2

Say 1:10

Will move 10 times faster into water and into lipid

10 times more hydrophilic

k2 is 10 times faster than k1

why does it matter?

Duodenum is aqueous

cell membrane is lipid

If a molecule kd=10, it will move 10 time faster into the cell membrane, but will be slow to leave

Kd=10 is the same as for every 10 molecules in the cell membrane, there is one in the duodenum and one in the blood

Drug should be between these so they do not get trapped in either cell compartment

If a molecule kd=0.14, it will move 14 time faster into the duodenum and the blood, but will not want to cross the membrane

kd=.14 is the same as for every 14 molecules in the duodenum and blood, there is one in the cell membrane

Blood plasma is aqueous

Protein binding

binds to protein in the blood (aqueous)

Reservoir for drug in the blood

can release drug from protein when free drug in blood is used up

Causes a shift in the equilibrium as the concentration for free drug in the blood drops

shift rate to favor moving molecule from the protein into the blood

the level of binding depends on the affinity of the drug for that plasma protein and extent of binding can range from 1 or 2 % up to 99%

most common albumin, but also various lipoproteins, glycoproteins and beta globulins

Increase protein binding increase lipophilicity

Plasma protein binding is saturable

drug saturation of the plasma protein makes a big difference to free drug concentrations

Doubling the dose from 400 to 800 micromolar doesn’t simply double the free concentration of drug in the circulation, it increases it almost exponentially

as less drug reaches the circulation is bound by the plasma proteins. Thus the unbound, free drug is increasingly available for subsequent reaction.

pH and ionization

ionization is the chance of a drug being in its uncharged or charged state

Tendency to Ionize

reversible

Dependent on the pH

Acidic antibiotics, the higher the pH the higher that chance it will ionize

stomach ph=2

acidic antibiotics will not ionize

retains it's uncharged form (acidic), and thus can exit its membrane space

duodenum pH= 6

ionizes the antibiotics (becomes like COO-)

can't cross out

Ion trapping

acidic antiobody accumulates in the duodenum

blood pH= 7

ionizes the antibiotic(becomes like COO-)

acts as a reservoir for drug in the blood

none of the drug can cross back into the membrane (Ion trapping)

drops the amount of drug in the duodenum since it cannot go back (less drug available to active transport)

Drug accumulates in the blood plasma

laws of mass action

used to describe a dissociation constant for these two states at equilibrium

note that we typically don't need exact percentages of protonation

we can use a protonation table, where pH-pka= HA as a fraction of total drug (or 1/ (10 ^ (pH-pka) +1)

BH+ counts as an ionized drug, thus less likely to be reabsorbed

AKA- protonation of an acid
tends to make the molecule neutral whilst protonation of a base charges that molecule.

This table take HA, the uncharged form, as protonated

pka= known for most drugs and most bodily fluids

ionized drugs tend to dissolve well in aqueous environments, while uncharged molecules can ravel well though lipid environments
aqueous fluids whilst uncharged forms of drugs, will more easily pass through lipid
membranes

Distribution

how the drug is passed along tissues and compartments

compartments

cytoplasm the chief reservoir for water soluble drugs

35%

plasma (5%) , body fat (20%) and interstitial water (15%)

act to a greater or lesser degree as reservoirs for drug dissolution

Trans‐cellular fluid

cerebrospinal, intraocular, peritoneal, pleural and synovial fluids and
digestive secretions

2%

volume

Apparent volume of distribution, apparent because in reality it doesn’t correspond to any real volume in the body.

assumes that there are two places for drug to reside inside the body: in the circulation and in everywhere else

good estimation of how well a drug is able to leave the circulation and penetrate into tissues

a blood sample can estimate whether a drug is primarily in the tissues
or in the circulation

A high VD suggests that the drug has left the circulation

A low VD suggests that the drug is primarily still in the circulation

The volume of fluid required to contain the full concentration of the drug dose(D), at the same concentration as present in the plasma

Blood brain barrier poses problems in drug distribution

Lacks fenestrations between endothelial cells

tight juctions mean that the drug has to pass two lipid membranes (lumenal and basolateral surfaces of the endothelial cells)

excludes large molcules

high lipophilic drugs can pass

diffusion is the primary method for molecular movement

solutes such as amino acids, glucose, amines and purines, are actively transported across the blood brain barrier by carriers

Excretion

Removal of the drug from the system

mostly occurs in the kidneys

most proteins and plasma protiens cannot pass the glomerular

Subtopic

Subtopic

excretion

usually through kidneys

goes through the glomerular membrane (lipid) by glomerular filtration

Protein retained

if drug is bound to protein, it will not be easily transported into the filtrate

this is a problem for warfarin, as it is 98% of the time bound to protein

rate of excretion of Warfarin will be slower than the rate of excretion of another drug with lower affinity for plasma proteins

more free drug available for ultrafiltration or to simply diffuse across the renal tubule

Drugs that are protein bound may still be
readily excreted via the carrier systems

penicillin is about 80% protein
bound, but almost entirely and rapidly excreted by the organic anion transporters

lose small molecules

free drug excreted

loss of the free drug shifts the equilibrum

causes the protein bound drug to be released to fill the loss concentration

over time all the drug will be excreted

can be reabsorbed

affected by the pH of the urine

Acidic urine reabsorbs more acidic antibodies

alkaline urine will cause more acidic free drug to ionize and be excreted

tubercle secretion

tubular secretion involves specific transporter proteins

99% of water exiting the circulation via glomerular filtration, is reabsorbed as the fluid passes along the tubule

drugs are passively reabsorbed along the concentration gradient created by the
concurrent resorption of water

Lipophilic drugs more able to cross membranes and are proportionately reabsorbed more than polar hydrophilic molecules

thus it can be antagonized

competitively inhibit loss of penicillin from the circulation.

excretion of other substrates can be slowed in this way, these include the non steroidal anti‐inflammatories ‐ indomethacin and naproxen‐, but also drugs as diverse as methotrexate, and antiretroviral Zidovudine and the anti‐influenza drug Tamiflu.

Best described by Clearance

is an indicator of efficiency of drug removal
from the plasma

volume of blood cleared of a drug through an organ per unit time (e.g. ml/min)

measure of the efficiency of the organs of elimination, in particular, the kidney,
and may therefore be considered a function of the wellness state of the patient

if it's low, we may have pathology in the excretory organs

Total body clearance is the sum of all the clearances by various mechanisms

number of drugs which are primarily excreted by the kidney

renal clearance=total body clearance

independent of the drug kinetic parameters, such as volume of distribution, bioavailability and drug half life

thus is a constant

Metabolism

Biotransfromation of the drug

Usually to inactivate it

main site for drug metabolism is the liver

Contains two phases

Phase 1

making it more water soluble, and so less able to be re‐absorbed by the renal tubule

Primarily Oxidation reactions and also reduction and hydrolysis.

Oxidation involves the addition of oxygen resulting in hydroxylation, oxidation, dealkylation or deamination, the net result
being to increase water solubility

mediated by cytochrome system associated with the cell's ER

found mostly in the liver

Cytochrome p450 enzymes are iron bearing haem proteins

a large superfamily with 74 gene families
referred to by the designation CYP followed by a number and letter designation

CYP1, CYP2, and CYP3 are the main drug metabolizers

member of these families generally has a
distinct but somewhat overlapping specificity for substrate, sometimes acting on the same substrate but at
different rates, for example

cytochrome p450 cycle adds oxygen or hydroxyl

individual patient response variation due to genetic variation in p450 enzymes

P450 enzyme levels are also readily regulated by external factors

Grapefruit can downregulate CYP3A4 and so inhibit the breakdown of some drugs

not all metabolized in the liver

neuromuscular blocker,succinylcholine, is metabolized by plasma cholinesterases and alcohol

metabolized by both CYP2A6 and
cytoplasmic alcohol dehydrogenase

more for non‐polar drugs than polar drugs, as they must be able to readily cross the cell membrane in order to reach the cytochrome systems

polar drugs are usually just excreted in the urine

Phase 2

altering its structure such that it reduces its intrinsic efficacy and so aids its excretion

Involves conjugation of site chains to drugs through glucuronidation, sulphation,
glutathione addition, glycine or even water conjugation and also methylation

produces a polar molecule that is readily excreted (inactive product)

groups such as glucuronyl, sulphate, methyl and acetyl are attached to the drug

bilirubin and adrenal corticosteroids are also conjugated by glucuronidation, addition of glucuronic acid

creations uridine diphosphate glucuronic acid (UDPGA), a high‐energy phosphate compound

takes place mainly in the liver,
but also lungs and kidneys

first pass effect

first pass effect is the metabolism of drugs prior to reaching the circulation

absorption from small intestine directly to the hepatic portal vein to the liver

EX. Lidocaine --> highly metabolized by liver enzymes and the first pass through the liver removes most of the active drug

thus lidocaine cannot be administered orally

can occur in Gastric mucosa

pro-drugs

metabloites made by metabolizing a drug that are more potent/active than the parent molecule

also more toxic

ex. acetominophen

mechanism

passive diffusion

majority of drug rely on diffusion

nonspecific movement

specific carriers (carries a single species in the direction of its
electrochemical gradient)

also a majority of drugs rely on

some are passive mediators of diffusion down a concentration gradient (facilitated diffusion)

organic cation transporters (OCTs) are a family of cation transporters with specificity for a large number of cationic substrates that are both endogenous and exogenous

mediate the movement of dopamine and choline but includes
some drugs such as vecuronium, quinine and procainamide

OCT2 associated with nephrotoxicity

found in proximal cells in the kidney and notably has cisplatin, the anti‐cancer drug as one of its substrates

transporter is directional and moves cisplatin from the circulation and into the
renal tubule with no way to move cisplatin back out (accumulation and then nephrotoxicity)
cytoplasm of the renal cell. As there is no specific transporter to remove the cisplatin. this
results in accumulation of the drug and ultimately in nephrotoxicity

Some use ATP in active transport

ATP Binding Cassette transporters (ABCs)

Made of p-glycoproteins

are responsible for many cases of drug
resistance in cancer, as they mediate removal of drugs from cells

In high quantity in the intestine, in the renal tubular brush border membranes and in the bile canaliculi

aquaporins

0.4nm in diameter allowing through only the smallest molecules

Too small for most drugs

pinocytosis

invagination of a piece of a cell membrane, which forms a vacuole with metabolite within

can release contents in the cell or be moved to the tother side of the cell and released into the extracellular space

only good for large molecules

One side could have more transports, the other side may have less

Floating topic

On administration, most drugs do not distribute evenly and rapidly throughout all the compartments mentioned here. This is a process that may happen in several stages for some drugs especially the lower
molecular weight drugs that more easily diffuse out of the circulation

Floating topic