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Module 4 Pharmacokinetics (distribution (compartments (transcellular water…
Module 4 Pharmacokinetics
absorption
drug movement across cell barriers
diffusion
lipid solubility
partition coefficient:
ratio of drug dissolution in oil/water
should be just lipophilic enough to pass through but not too lipophilic
size: must not be too large
pH/ionization
crosses membrane when non-ionized
ion trapping
:
ionization preference and retention of a drug in a compartment favoring it's ionization and dissolution
acidic drug compartmentalizes in high pH
aspirin ionization
gastric juice < plasma < urine
basic drug compartmentalizes in low pH
pethidine/mepiridine ionization
: gastric juice > plasma > urine
henderson-hasselbalch eq
basically pH - pKa = log(ratio of basic form to acidic form)
for basic drugs the ionized form is the protonated/acid form BH+ for acidic drugs the ionized form is the basic form/deprotonated A-
solute carrier/membrane transporter mediated processes
solute carriers
(gradient dependent)
passive mvmt
down gradients for a specific solute
structurally related organic cation transporter (OCT) and organic anion transporter (OAT)
OCTs
dopamine, choline, veruconium, quinine, procainamide
OCT2 : @ proximal calls in kidney, cisplatin (anti-cancer drug)
ATP-binding cassete (ABC) transporters
active transport against concentration gradients
P-glycoprotein transporters
responsible for drug resistances in cancer
@ high conc in intestine, renal tubular brush border membranes, and bile canaliculi
polymorphic variation
aqueous pores: 0.4nm; not for drugs
pinocytosis: very large molecules; vacuolization
distribution
compartments
cytoplasm =
chief reservoir for water soluble drugs, 35%
plasma = 5%
body fat = 20%
interstitial water = 16*
transcellular water = 2%
CSF
intraocular
peritoneal
pleural
synovial fluid
digestive secretion
volume of distribution
Vd= apparent volume of distribution; assumes drug is either in circulation or everywhere else in the body = volume of fluid req to contain the total amt D at the same conc as present in the plasma
D = dose; C0 = plasma conc at time zero
low Vd = primarily in the plasma
Blood Brain Barrier
no fenestrations = difficult solute passage
diffusion
: highly lipophilic drugs
active transport
amino acids
glucose
amines
purines
metabolism
locations
primarily
liver
Phase 1:
cytochrome p450 enzymes
: iron bearing heme proteins; superfamily w/ 74 gene families; net effect - addition of oxygen or hydroxyl
CYP1, CYP2, CYP3
= primary drug metabolizing enzymes
external regulation
grapefruit juice
: CYP3A4 down regulated = inhibition of breakdown of some drugs by CYP3A4
brussel sprouts, cigarette smoke
: induce p450 enzymes & increase drug breakdown
in plasma and other tissues
succinylcholine
: metabolized by plasma cholinesterases
alcohol
: metabolized by CYP2A6 in the liver
and
cytoplasmic alcohol dehydrogenase
processes
Phase 1
: increase water solubility of drug:
less able to be reabsorbed by the renal tubule
oxidation
addition of oxygen --> hydroxylation, oxidation, dealkylation or deamination = inc water solubility
@ cytochrome system assoc = w/ ER;
cytochrome p540 enzymes
reduction
hydrolysis
Phase 2
: alter structure to reduce intrinsic efficacy :
aids in excretion
conjugation
of site chains to drugs; typically producing a polar molecule that is readily excreted
glucuronidation
sulphation
glutathione addition
glycine/water conjugation
methylation
examples
acetaminophen: NAPQI +
glutathione
bilirubin and adrenal corticosteroids :
glucuronidation
= glucuronide formation:
UDPGA = uridine diphosphate glucuronic acid
--> transfer glucuronic acid to substrate
UDP-glucuronyl transferase
first pass effect & pro drugs
first pass effect
: absorption from small intestine direct to hepatic portal vein to liver = primary site of metabolism
lidocaine
pro-drugs
: inactive drug precursor --> full drug activity afte metabolic processing; more active metabolites than original molecules
acetaminophen
elimination
excretion
hepatic route
from plasma to bile via SLC and P-gp transporters
enterohepatic circulation --> re-uptake excreted drugs
renal route (majority):
pH and ionization dependent
glomerular filtration
smaller that mw 500-15000 readily pass and cleared
plasma protein bound drugs not filtered bc plasma proteins do not pass
active tubular secretion
via carriers (OAT, OCT)
passive diffusion across tubular epithelium
highly lipophilic drugs or those non-ionized in urine
feces, breath, sweat, saliva, tears, breast milk (minimal)
plasma clearance (Cl)
: volume of blood cleared of a drug through an organ per unit time;
ml/min
independent of kinetic parameters (Vd, bioavailability, drug half life) = constant
accounts for resorption and glomerular filtration
reduced clearance could indicate impaired kidney fxn or other excretory organ
