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Module 4 Pharmacokinetics By Lauren McCormick (Metabolism (First Pass…
Module 4
Pharmacokinetics
By Lauren McCormick
Absorption
Where? From the site of administration
What? Drug movement across cell barriers
How?
Passive movement
Active transport
Majority: non-specific diffusion
Diffusion through lipid membranes
lipid solubility determines how well & how much of a drug passes through membrane
experimentally determined
partition co-efficient
: ratio of drug dissolving in oil/water
too lipid soluble --> will not pass through lipid membrane
pH & ionization
weak acid/weak base drugs
ionized or uncharged depending on pH of surrounding environment
ionized drugs dissolve well in aqueous fluids
uncharged drugs more easily pass through lipid membranes
knowing pKa & pH
estimate what proportion of drug will be ionized & therefore how much of the drug will cross lipid membrane
pH differences
gradients of drug accumulation
weakly acidic aspirin accumulates in compartments w/ high pH
weakly basic pethidine/mepiridine tends to accumulate in compartments of low pH
Majority of the rest: specific carrier
Organic cation/anion transporters
Solute Carriers (SLC)
passive movement of solutes down gradients
structurally related Organic Cation Transporter (OCT) & Organic Anion Transporter (OAT)
electrochemical gradient
imporant for transfer at BBB, GIT, renal tubule
specialized transporter complexes
mediate cell uptake & movement across membranes
ATP-binding cassette (ABC) transporters
P-glycoproteins (P-gp)
aberrant expression may cause multidrug resistance in cancer
often co-located w/ SLC transporters as "reverse pumps"
against the concentration gradient
plasma proteins
drug binding results in non-linear increases in free-drug concentrations in plasma
high conc drugs can saturate binding sites on proteins
competition for binding on plasma proteins
high affinity drugs displace low affinity drugs
although most drugs not in large enough quantities for displacement to be a significant factor in free concentration
ex. predominantly albumin
Small water soluble molecules: aqueous pores
Pinocytosis: large molecules
Distribution
Where? Within the body to organs and tissues
aqueous compartments
aqueous cytoplasm of cells = chief reservoirs for water soluble drugs
other compartments act as reservoirs for drug dissolution
plasma
body fat
interstitial water
Blood Brain Barrier
Non-brain capillary: fenestrations in endothelial cell lined blood vessels
Brain capillary: tight junctions so solutes must pass through two lipid membranes
most drugs & large molecules excluded
highly lipophilic drugs may cross BBB
What? continual process of drug distribution into liquid or aqueous
compartments
of the body
Volume of Distribution (Vd)
D = dose
C0 = plasma concentration at time zero
comparing volume in circulation and everywhere else
blood samples allow us to estimate where drug primarily resides
High
: drug has left circulation
Low
: drug primarily still in circulation
does NOT take into account metabolism of drug
relevant immediately after administration
Metabolism
What? Biotransformation of drug, often inactivating
Drug --> Derivative --> Conjugate
prepares drug for elimination by making it more water soluble
Where? liver is the main site of metabolism
Stages:
Phase 1
primarily oxidation
increase water solubility
primarily mediated by cytochrome system associated w/ ER in cells
takes place mainly in the liver
genetic variation of p450 enzyme
primary causes of individual patient response variation
primary drug metabolizing enzymes =
CYP1, CYP2, CYP3
cytochrome p450 enzymes
iron bearing haem proteins
net effect of action is addition of oxygen or hydroxyl
reduction & hydrolysis too
add a reactive residue to processed molecule
can turn inactive pro-drug into active drug
can create a reactive toxic metabolite from another drug
Phase 2
conjugation of side chains to drugs
glucuronidation, sulphation, glutathione addition, glycine or water conjugation, methylation
produces polar molecule that is readily excreted
reactive group from Phase 1 may act as a target site for conjugation system of Phase 2
mainly take place in liver
First Pass Effect
metabolism of drugs prior to reaching circulation
absorption from small intestine direct to hepatic portal vein
bioavailability= drug that reaches circulation
Drugs most affected
ex. lidocaine
active drug removed in liver during first pass
must be injected near target site, can't be administered orally
Prodrugs
inactive drug precursors that utilize the first pass effect to produce an active drug
Excretion
What? Removal of drug or drug metabolite from the body
via
Hepatic Route
transport of drugs from plasma to bile via SLC & P-gp transporters
enterohepatic circulation can re-uptake excreted drugs
Renal Route
glomerular filtration
molecules <5,000-15,000mw readily pass
plasma proteins like albumin do not pass
plasma protein-bound drug will therefore not pass
active tubular secretion
transport via carriers (OAT, OCT)
passive diffusion across tubular epithelium
highly lipophilic drugs or those non-ionized in urine may be resorbed
pH control of drug excretion
99% of water exiting circulation via glomerular filtration is reabsorbed as fluid passes along tubule
drugs are passively reabsorbed along concentration gradient made by resorption of water
ion trapping
increased basic drug excretion in acidic urine
increases acidic drug excretion in alkaline urine
clearance
- drug excretion by liver or kidneys
Plasma clearance
(Cl) = volume of plasma cleared of drug per unit time (ml/min)
indicator of efficiency of drug removal from plasma
total body clearance = sum of all the clearances by various mechanisms
primary excretion via urine, but also feces, breath, sweat, saliva, tears, breast milk
